WO2013064702A2 - Probes for diagnosis and monitoring of neurodegenerative disease - Google Patents

Abstract

The present invention relates to oligonucleotide probes and their use in assessing gene transcript levels in a sample, which may be used in analytical techniques, particularly to identify, diagnose or monitor neurodegenerative diseases or conditions and their progression, particularly Alzheimer's disease and mild cognitive impairment.

Description

Probes for diagnosis and monitoring of neurodegenerative disease

The present invention relates to oligonucleotide probes, for use in assessing gene transcript levels in a sample, which may be used in analytical techniques, particularly diagnostic techniques. Conveniently the probes are provided in kit form. Different sets of probes may be used in techniques to prepare gene expression patterns and identify, diagnose or monitor neurodegenerative diseases or conditions and their progression.

Neurodegenerative disease results in the progressive degeneration and/or death of nerve cells leading to problems with movement (ataxias) or mental functioning (dementias). In particular the method is concerned with identifying, diagnosing or monitoring cognitive impairment and its progression, e.g. to dementias such as Alzheimer's disease or stages thereof.

Dementias account for the majority of neurodegenerative diseases in the population. The prevalence of dementia is rapidly rising as the average age of the population increases. It is estimated that more than 24 million people worldwide have dementia. Alzheimer's disease accounts for the highest number of dementia cases, particularly in the elderly.

Evidence suggests that the pathophysiological process of dementia, e.g. Alzheimer's disease, begins years, if not decades, prior to the diagnosis of clinical dementia.

Therapeutic interventions early in the pathophysiological process are more likely to be successful, particularly as treatments of Alzheimer's disease appear to have limited impact once the clinical symptoms appear and neuronal degradation has begun.

Thus, there is a need to identify patients that might progress to ataxia or dementia as soon as possible so that treatment and management strategies may be contemplated at an early stage. Current methods for detecting dementias have poor positive predictive accuracy of up to about 61 % (Visser, 2006, Principles & Practice of Geriatric Medicine, 4th Edition, Eds. Pathy et al., Section 94).

In Alzheimer's disease and other dementias, the earliest clinical sign of the presence of a cognitive disorder is mild cognitive impairment (MCI) which is a predementia phase of cognitive dysfunction.

MCI is a general term that defines a mildly impaired set of patients which show reduced cognitive performance. MCI patients may be divided into amnestic MCI and non- amnestic MCI but even this is not predictive of whether the MCI will progress to dementia. Not all forms of MCI will evolve into a dementia such as Alzheimer's disease and some may be stable or exhibit improvement with time. Thus MCI describes a group of patients grouped by clinical parameters rather than the underlying pathology. Within that group are sub-groups that will convert to Alzheimer's disease, that will convert to other dementias, which are stable or which will revert to normal cognitive function.

The sub-group of MCI patients that convert to dementia may be considered prodromal for that dementia, e.g. to have prodromal Alzheimer's disease (AD). It is generally accepted that the progression rate of patients with MCI to AD is between 10 and 15% per year but to date there is no reliable and easy way of identifying the sub-group that will convert.

Methods for identifying whether a patient will progress from MCI to Alzheimer's disease include assessment of various predictors of progression such as the ApoE ε4 carrier status, presence of atrophy on MRI, 18FDG PET pattern of Alzheimer's disease, presence of CSF markers (such as amyloid β1 -42 peptide, total tau and phosphorylated tau) and a positive amyloid imaging scan (see Petersen et al., 2009, Arch. Neurol., 66(12), p1447- 1454). However, whilst these predictors may be associated with Alzheimer's disease they are not always specific to Alzheimer's disease and more than one marker is usually necessary to aid diagnosis, particularly coupled with cognitive testing.

As mentioned above, to allow for early therapeutic intervention, early identification of neurodegnerative diseases or conditions is important, e.g. the identification of MCI patients that will progress to dementia. Okamura et al., 2002, Am. J. Psychiatry, 159:3, p474-476 used a combined test of CSF tau levels and regional cerebral blood flow in the posterior cingulate cortex. However, such methods are time consuming, complex and invasive with high cost and low patient compliance making introducing such diagnostic tools in a wide clinical setting challenging. Furthermore, cognitive markers have been found to be better predictors of conversion to dementia (Gomar et al., 201 1 , Arch. Gen Psychiatry, 68(9); p961 - 969). A simple test to identify and stage neurodegenerative disorders and diseases, particularly in relation to Alzheimer's disease would be desirable. Determination of whether dementia may be attributed to Alzheimer's disease or another cause would also be useful. In particular the use of an accurate blood based test would clearly be a valuable asset in the assessment of patients with possible neurodegenerative diseases or conditions.

In earlier work, the present inventors identified the systemic effect of various diseases and conditions on gene expression in blood cells, see e.g. W098/49342 and WO04/046382, incorporated herein by reference, the latter of which describes specific probes for the diagnosis of breast cancer and Alzheimer's disease. Blood tests based on gene expression profiling in the diagnosis of brain disorders have been described. In particular, the present inventors have identified that the expression of 96 genes allows the detection of patients with Alzheimer's disease (Rye et al., 201 1 , Journal of Alzheimer's Disease, 23, p121 -129). However, these methods have not allowed for the determination of the stage or progression of the disease or for the identification of the sub-group within MCI patients that will progress to dementia. The identification of quick and easy methods of sample analysis for, for example, diagnostic applications, remains the goal of many researchers. End users seek methods which are cost effective, produce statistically significant results and which may be implemented routinely without the need for highly skilled individuals.

We have now identified sets of probes which are of surprising utility for identifying, staging and monitoring neurodegenerative diseases and conditions, particularly Alzheimer's disease.

In work leading up to this invention, the inventors examined the level of expression of various genes in patients with neurodegenerative diseases at various stages relative to normal patients.

Thus in one aspect, the present invention provides a set of oligonucleotide probes, wherein said set comprises at least 10 oligonucleotides, wherein each of said 10

oligonucleotides, which are each different, are selected from:

(a) an oligonucleotide which is a part of a sequence as set forth in Table 1 ;

(b) an oligonucleotide derived from a sequence as set forth in Table 1 ;

(c) an oligonucleotide with a sequence complementary to the sequence of the oligonucleotide of a) or b); or

(d) an oligonucleotide which is functionally equivalent to an oligonucleotide as defined in (a), (b) or (c).

As referred to herein, a sequence as set forth in Table 1 is the sequence to which the assay refers, e.g. ASSAY0001 refers to SEQ ID No. 1 provided herein. Table 1 consists of two Tables, namely Table 1 a and Table 1 b and all references herein to Table 1 extend to Table 1 a and/or Table 1 b. Table 1 a is the list of Assays provided in Table 1 , excluding Assays 0146, 0188, 0208, 0229, 0260 and 0276 (six Assays which are present in Table 22). Table 1 b is the full list of Assays provided in Table 1 .

An oligonucleotide which is part of said sequence has the size as described hereinafter and satisfies the requirements of the oligonucleotide probes as described herein, e.g. in length and function. Such oligonucleotides include probes such as primers which correspond to a part of the disclosed sequence or the complementary sequence. More than one oligonucleotide may be a part of the sequence, e.g. to generate a pair of primers and/or a labelling probe.

In a preferred aspect the oligonucleotide has the sequence set forth in the context sequence for said full length sequence or a part thereof as described herein, wherein said context sequence is a portion of the full length sequence and is provided in Tables 2 to 1 1 or 22 (preferably Tables 2 to 9) in relation to the relevant sequence and is referred to herein as the oligonucleotide sequence from said Tables. As referred to herein, an oligonucleotide from a Table (or a Table oligonucleotide or probes) refers to an oligonucleotide which is a part of a sequence (oligonucleotide or full length) as set forth in a Table or its derived, complementary or functionally equivalent oligonucleotides.

Preferably, each of said 10 probes is part of a different sequence as set forth in Table 1 , but one or more of said oligonucleotides may be replaced by the corresponding complementary or functionally equivalent oligonucleotide, i.e. replaced with an

oligonucleotide that will bind to the same gene transcript. If, for example, only primers are to be used, in all likelihood all oligonucleotides will be parts of the provided sequences.

In a preferred aspect, said set comprises at least 15, 20, 30, 40, 50, 60 or especially preferably all of the probes of Table 1.

In particularly preferred aspects the probes may be from Tables 2 to 1 1 or 22 (preferably Tables 2 to 9) as described hereinafter.

Conveniently the 10 or more probes which are selected are probes which are common to one or more of the Tables described herein. Thus, preferably said 10 or more probes are selected from probes which appear in both Tables 2 and 3 (in particular in relation to MCI stable versus converter analysis discussed hereinafter) or in both of Tables 9 and 10 (in particular in relation to determining the progression of Alzheimer's disease). In preferred alternative aspects, in Tables in which only some sequences exhibit a p-value of <0.5, the 10 or more probes may be selected from that group. These probes thus provide core probes to which additional probes may be added from relevant Tables. Each table of probes may also form a core group of probes (e.g. Table 3), to which additional probes may be added, e.g. one or probes from Table 2, in particular those exhibiting a p-value of <0.5.

These probes do not rely on the development of disease to clinically recognizable levels and allow detection of a neurodegenerative disease or disorder at a very early stage, even years before other subjective or objective symptoms appear.

The use of such probes in products and methods of the invention, form further aspects of the invention as described hereinafter. As referred to herein an "oligonucleotide" is a nucleic acid molecule having at least 6 monomers in the polymeric structure, i.e. nucleotides or modified forms thereof. The nucleic acid molecule may be DNA, RNA or PNA (peptide nucleic acid) or hybrids thereof or modified versions thereof, e.g. chemically modified forms, e.g. LNA (Locked Nucleic acid), by methylation or made up of modified or non-natural bases during synthesis, providing they retain their ability to bind to complementary sequences. Such oligonucleotides are used in accordance with the invention to probe target sequences and are thus referred to herein also as oligonucleotide probes or simply as "probes".

"Probes" as referred to herein are oligonucleotides which bind to the relevant transcript and which allow the presence or amount of the target molecule to which they bind to be detected. Such probes may be, for example probes which act as a label for the target molecule (referred to hereinafter as labelling probes) or which allow the generation of a signal by another means, e.g. a primer.

As referred to herein a "labelling probe" refers to a probe which binds to the target sequence such that the combined target sequence and labelling probe carries a detectable label or which may otherwise be assessed by virtue of the formation of that association. For example, this may be achieved by using a labelled probe or the probe may act as a capture probe of labelled sequences as described hereinafter.

When used as a primer, the probe binds to the target sequence and optionally together with another relevant primer allows the generation of an amplification product indicative of the presence of the target sequence which may then be assessed and/or quantified. The primer may incorporate a label or the amplification process may otherwise incorporate or reveal a label during amplification to allow detection. Any oligonucleotides which bind to the target sequence and allow the generation of a detectable signal directly or indirectly are encompassed.

"Primers" refer to single or double-stranded oligonucleotides which hybridize to the target sequence and under appropriate conditions (i.e. in the presence of nucleotides and an inducing agent such as a DNA polymerase and at a suitable temperature and pH) act as a point of initiation of synthesis to allow amplification of the target sequence through elongation from the primer sequence e.g. via PCR.

In primer based methods, preferably real time quantitative PCR is used as this allows the efficient detection and quantification of small amounts of RNA in real time. The procedure follows the general RT-PCR principle in which mRNA is first transcribed to cDNA which is then used to amplify short DNA sequences with the help of sequence specific primers. Two common methods for detection of products in real-time PCR are: (1 ) non- specific fluorescent dyes that intercalate with any double-stranded DNA, for example SYBR green dye and (2) sequence-specific DNA probes consisting of oligonucleotides that are labelled with a fluorescent reporter which permits detection only after hybridization of the probe with its complementary DNA target for example the ABI TaqMan System (which is discussed in more detail in the Examples).

An "oligonucleotide derived from a sequence as set forth in Table 1 " (or any other table) includes an oligonucleotide derived from the genes corresponding to the sequences (i.e. the presented oligonucleotides or the listed gene sequences) provided in those tables, i.e. to provide oligonucleotides which bind to transcripts from the same gene as the gene to whose transcripts the oligonucleotide of Table 1 binds, preferably which bind to the same transcript but in the alternative derived oligonucleotides may bind to splicing variants.

Tables 2 to 1 1 and 22 (preferably Tables 2 to 9) provides gene identifiers for the various sequences (i.e. the gene sequence corresponding to the sequence provided). Details of the genes may be obtained from the Panther Classification System for genes, transcripts and proteins (http://www.pantherdb.org/qenes). Alternatively details may be obtained directly from Applied Biosystems Inc., CA, USA. In this case the oligonucleotide forms a part of the gene sequence of which the sequence provided in any one of Tables 2 to 1 1 and 22 (preferably Tables 2 to 9) is a part. Thus the derived oligonucleotide may form a part of said gene (or its transcript). Thus, for example, labelling probe or primer sequences may be derived from anywhere on the gene to allow specific binding to that gene or its transcript. Thus in a preferred aspect said derived oligonucleotide is an oligonucleotide that is complementary to and binds to a gene as set forth in any one of Tables 1 to 1 1 and 22 (preferably Tables 1 to 9) or the complementary sequence of said gene.

Preferably the oligonucleotide probes forming said set (and hence the part of the sequence provided in the Tables) are at least 15 bases in length to allow binding of target molecules. Especially preferably said oligonucleotide probes are at least 10, 20, 30, 40 or 50 bases in length, but less than 200, 150, 100 or 50 bases, e.g. from 20 to 200 bases in length, e.g. from 30 to 150 bases, preferably 50-100 bases in length.

When that probe is a primer, similar considerations apply, but preferably said primers are from 10-30 bases in length, e.g. from 15-28 bases, e.g. from 20-25 bases in length. Usual considerations apply in the development of primers, e.g. preferably the primers have a G+C content of 50-60% and should end at the 3'-end in a G or C or CG or GC to increase efficiency, the 3'-ends should not be complementary to avoid primer dimers, primer self- complementarity should be avoided and runs of 3 or more Cs or Gs at the 3' ends should be avoided. Primers should be of sufficient length to prime the synthesis of the desired extension product in the presence of the inducing agent.

To identify appropriate primers for performance of the invention, the gene sequences or oligonucleotide sequences provided in Tables 1 to 1 1 or 22 (preferably Tables 1 to 9) may be used to design primers or probes. Preferably said primers are generated to amplify short DNA sequences (e.g. 75 to 600 bases). Preferably short amplicons are amplified, e.g.

preferably 75-150 bases. The probes and primers can be designed within an exon or may span an exon junction. For example, Tables 2 to 1 1 and 22 (preferably Tables 2 to 9) provides the ABI Taqman Assay ID that can be used to obtain additional information pertaining to Assay IDs from the supplier web page

httpi//www.appliedbiosvstems.com/absite/us/en/home/applications-technoloqies/real ime- pcr/taaman-probe-based-aene-expression-analvsis/taaman-qene-expression-assav- selection-quide.html. Once Taqman assays has been identified they can then be obtained from the supplier. Alternatively, the gene names and gene symbols can be used to identify the corresponding gene sequences in public databases, for example The National Center for Biotechnology Information (http://www.ncbi.nlm.nih.qov/). Alternatively, the oligonucleotide nucleotide sequences provided may be used to identify corresponding gene and transcript by aligning them to known sequences using Nucleotide Blast (Blastn) program at NCBI. Using the gene or transcript sequence, primers and probes can be designed by using freely or commercially available programs for oligonucleotide and primer design, for example The Primer Express Software by Applied Biosystems.

As referred to herein the term "complementary sequences" refers to sequences with consecutive complementary bases (i.e. T:A, G:C) and which complementary sequences are therefore able to bind to one another through their complementarity.

Reference to "10 oligonucleotides" refers to 10 different oligonucleotides. Whilst a Table 1 oligonucleotide, a Table 1 derived oligonucleotide and their functional equivalent are considered different oligonucleotides, complementary oligonucleotides are not considered different. Preferably however, the at least 10 oligonucleotides are 10 different Table 1 oligonucleotides (or Table 1 derived oligonucleotides or their functional equivalents). Thus said 10 different oligonucleotides are preferably able to bind to 10 different transcripts.

Preferably said oligonucleotides are as set forth in Table 1 or are derived from a sequence set forth in Table 1. Said derived oligonucleotides include oligonucleotides derived from the genes corresponding to the sequences provided in those tables, or the complementary sequences thereof. In a preferred aspect, said oligonucleotides are as set forth in any one of Tables 2 to 1 1 and 22 (preferably Tables 2 to 9) or are derived from, complementary to or functionally equivalent to such oligonucleotides. Thus when the text refers to Table 1 , this may equally be considered to refer to any of Tables 2 to 1 1 and 22 (preferably Tables 2 to 9) in preferred embodiments.

In a preferred embodiment, said set contains all of the probes (i.e. oligonucleotides) of any one of Tables 1 to 1 1 and 22 (preferably Tables 1 to 9) (or their derived,

complementary sequences, or functional equivalents) or of the sub-sets described above or below. Thus in one aspect the set may contain all of the probes of any one of Tables 1 to 1 1 and 22 (preferably Tables 1 to 9) (or their derived, complementary sequences, or functional equivalents), i.e. oligonucleotides from all of the sequences sets forth in any one of Tables 1 to 1 1 and 22 (preferably Tables 1 to 9), or derived, complementary or functionally equivalent oligonucleotides thereof. In a preferred aspect the sets consist of only the above described probes (or their derived, complementary sequences, or functional equivalents).

In addition to the above described informative probes the set may contain one or more reference probes (also referred to herein as assays) which may be used to normalize or pre-process the gene expression data. For example beta-actin has been used in the methods described herein which has been found to be preferable for TaqMan data on the platforms tested.

A "set" as described herein refers to a collection of unique oligonucleotide probes (i.e. having a distinct sequence) and preferably consists of less than 1000 oligonucleotide probes, especially less than 500, 400, 300, 200 or 100 probes, and preferably more than 10, 20, 30, 40 or 50 probes, e.g. preferably from 10 to 500, e.g. 10 to 100, 200 or 300, especially preferably 20 to 100, e.g. 30 to 100 probes. In some cases less than 10 probes may be used, e.g. from 2 to 9 probes, e.g. 5 to 9 probes. As described hereinafter, in methods of the invention such sets may be used in the presence of other probes and the signal from those other probes may be ignored or not used in classification analyses. In such cases the sets may additionally consist of such secondary, non-informative probes as described in more detail hereinafter.

It will be appreciated that increasing the number of probes will prevent the possibility of poor analysis, e.g. misdiagnosis by comparison to other diseases or stages thereof which could similarly alter the expression of the particular genes in question. Other oligonucleotide probes not described herein may also be present, particularly if they aid the ultimate use of the set of oligonucleotide probes. However, preferably said set consists only of said Table 1 (or other Table) oligonucleotides, Table 1 (or other Table) derived oligonucleotides, complementary sequences or functionally equivalent oligonucleotides, or a sub-set (e.g. of the size and type as described above or below) thereof.

Multiple copies of each unique oligonucleotide probe, e.g. 10 or more copies, may be present in each set, but constitute only a single probe.

A set of oligonucleotide probes, which may preferably be immobilized on a solid support or have means for such immobilization, comprises the at least 10 oligonucleotide probes selected from those described hereinbefore. As mentioned above, these 10 probes must be unique and have different sequences. Having said this however, two separate probes may be used which recognize the same gene but reflect different splicing events. However oligonucleotide probes which are complementary to, and bind to distinct genes are preferred.

When probes of the set are primers, in a preferred aspect pairs of primers are provided. In such cases the reference to the oligonucleotides that should be present (e.g. 10 oligonucleotides) should be scaled up accordingly, i.e. 20 oligonucleotides which correspond to 10 pairs of primers, each pair being specific for a particular target sequence. In a further alternative, the probes of the set may comprise both labelling probes and primers directed to a single target sequence (e.g. for the Taqman assay described in more detail hereinafter). In this case the reference to oligonucleotides that should be present (e.g. 10

oligonucleotides) should be scaled up to 30 oligonucleotides, i.e. 10 pairs of primers and a corresponding relevant labelled probe for a particular target sequence.

Thus in a preferred aspect the set of the invention comprises at least 20

oligonucleotides and said set comprises pairs of primers in which each oligonucleotide in said pair of primers binds to the same transcript or its complementary sequence and preferably each of the pairs of primers bind to a different transcript. In a further preferred aspect the invention provides a set of oligonucleotide probes which comprises at least 30 oligonucleotides and said set comprises pairs of primers and a labelled probe for each pair of primers in which each oligonucleotide in said pair of primers and said labelled probe bind to the same transcript or its complementary sequence and preferably each of the pairs of primers and the labelled probe bind to different transcripts. The labelled probe is "related" to its pair of primers insofar as the primers bind up or downstream of the target sequence to which the labelled probe binds on the same transcript.

As described herein a "functionally equivalent" oligonucleotide to those set forth in Table 1 (or other Tables) or derived therefrom refers to an oligonucleotide which is capable of identifying the same gene as an oligonucleotide of Table 1 or derived therefrom, i.e. it can bind to the same mRNA molecule (or DNA) or a splice variant transcribed from a gene (target nucleic acid molecule) as the Table 1 oligonucleotide or the Table 1 derived oligonucleotide (or its complementary sequence) but does not have precise complementarity to the mRNA or DNA (unlike derived sequences). Preferably said functionally equivalent oligonucleotide is capable of recognizing, i.e. binding to the same splicing product as a Table 1 oligonucleotide or a Table 1 derived oligonucleotide. Preferably said mRNA molecule is the full length mRNA molecule which corresponds to the Table 1 oligonucleotide or the Table 1 derived oligonucleotide.

As referred to herein "capable of binding" or "binding" refers to the ability to hybridize under conditions described hereinafter.

Alternatively expressed, functionally equivalent oligonucleotides (or complementary sequences) have sequence identity or will hybridize, as described hereinafter, to a region of the target molecule to which molecule a Table 1 oligonucleotide or a Table 1 derived oligonucleotide or a complementary oligonucleotide binds. Preferably, functionally equivalent oligonucleotides (or their complementary sequences) hybridize to one of the mRNA sequences which corresponds to a Table 1 oligonucleotide or a Table 1 derived oligonucleotide under the conditions described hereinafter or has sequence identity to a part of one of the mRNA sequences which corresponds to a Table 1 oligonucleotide or a Table 1 derived oligonucleotide. A "part" in this context refers to a stretch of at least 5, e.g. at least 10 or 20 bases, such as from 5 to 100, e.g. 10 to 50 or 15 to 30 bases.

In a particularly preferred aspect, the functionally equivalent oligonucleotide binds to all or a part of the region of a target nucleic acid molecule (mRNA or cDNA) to which the Table 1 oligonucleotide or Table 1 derived oligonucleotide binds. A "target" nucleic acid molecule is the gene transcript or related product e.g. mRNA, or cDNA, or amplified product thereof. Said "region" of said target molecule to which said Table 1 oligonucleotide or Table 1 derived oligonucleotide binds is the stretch over which complementarity exists. At its largest this region is the whole length of the Table 1 oligonucleotide or Table 1 derived oligonucleotide, but may be shorter if the entire Table 1 sequence or Table 1 derived oligonucleotide is not complementary to a region of the target sequence.

As referred to herein any reference to Table 1 may equally be interpreted as applying to any one of Tables 2 to 1 1 and 22 (preferably Tables 2 to 9).

Preferably said part of said region of said target molecule is a stretch of at least 5, e.g. at least 10 or 20 bases, such as from 5 to 100, e.g. 10 to 50 or 15 to 30 bases. This may for example be achieved by said functionally equivalent oligonucleotide having several identical bases to the bases of the Table 1 oligonucleotide or the Table 1 derived

oligonucleotide. These bases may be identical over consecutive stretches, e.g. in a part of the functionally equivalent oligonucleotide, or may be present non-consecutively, but provide sufficient complementarity to allow binding to the target sequence.

Thus in a preferred feature, said functionally equivalent oligonucleotide hybridizes under conditions of high stringency to a Table 1 oligonucleotide or a Table 1 derived oligonucleotide or the complementary sequence thereof. Alternatively expressed, said functionally equivalent oligonucleotide exhibits high sequence identity to all or part of a Table 1 oligonucleotide. Preferably said functionally equivalent oligonucleotide has at least 70% sequence identity, preferably at least 80%, e.g. at least 90, 95, 98 or 99%, to all of a Table 1 (or any of Tables 2 to 1 1 and 22, preferably Tables 2 to 9) oligonucleotide or a part thereof (or all or part of a sequence set forth in any of those Tables). As used in this context, a "part" refers to a stretch of at least 5, e.g. at least 10 or 20 bases, such as from 5 to 100, e.g. 10 to 50 or 15 to 30 bases, in said Table 1 oligonucleotide. Especially preferably when sequence identity to only a part of said Table 1 oligonucleotide is present, the sequence identity is high, e.g. at least 80% as described above.

Functionally equivalent oligonucleotides which satisfy the above stated functional requirements include those which are derived from the Table 1 oligonucleotides and also those which have been modified by single or multiple nucleotide base (or equivalent) substitution, addition and/or deletion, but which nonetheless retain functional activity, e.g. bind to the same target molecule as the Table 1 oligonucleotide or the Table 1

oligonucleotide from which they are further derived or modified. Preferably said modification is of from 1 to 50, e.g. from 10 to 30, preferably from 1 to 5 bases. Especially preferably only minor modifications are present, e.g. variations in less than 10 bases, e.g. less than 5 base changes.

Within the meaning of "addition" equivalents are included oligonucleotides containing additional sequences which are complementary to the consecutive stretch of bases on the target molecule to which the Table 1 oligonucleotide or the Table 1 derived oligonucleotide binds. Alternatively the addition may comprise a different, unrelated sequence, which may for example confer a further property, e.g. to provide a means for immobilization such as a linker to bind the oligonucleotide probe to a solid support.

Particularly preferred are naturally occurring equivalents such as biological variants, e.g. allelic, geographical or allotypic variants, e.g. oligonucleotides which correspond to a genetic variant, for example as present in a different species.

Functional equivalents include oligonucleotides with modified bases, e.g. using non- naturally occurring bases. Such derivatives may be prepared during synthesis or by post production modification. "Hybridizing" sequences which bind under conditions of low stringency are those which bind under non-stringent conditions (for example, 6x SSC/50% formamide at room temperature) and remain bound when washed under conditions of low stringency (2 X SSC, room temperature, more preferably 2 X SSC, 42°C). Hybridizing under high stringency refers to the above conditions in which washing is performed at 2 X SSC, 65°C (where SSC = 0.15M NaCI, 0.015M sodium citrate, pH 7.2).

"Sequence identity" as referred to herein refers to the value obtained when assessed using ClustalW (Thompson et al., 1994, Nucl. Acids Res., 22, p4673-4680) with the following parameters:

Pairwise alignment parameters - Method: accurate, Matrix: IUB, Gap open penalty: 15.00, Gap extension penalty: 6.66;

Multiple alignment parameters - Matrix: IUB, Gap open penalty: 15.00, % identity for delay: 30, Negative matrix: no, Gap extension penalty: 6.66, DNA transitions weighting: 0.5.

Sequence identity at a particular base is intended to include identical bases which have simply been derivatized.

As described above, conveniently said set of oligonucleotide probes may be immobilized on one or more solid supports. Single or preferably multiple copies of each unique probe are attached to said solid supports, e.g. 10 or more, e.g. at least 100 copies of each unique probe are present. Furthermore, as described hereinafter, the set of probes may be contained in platforms containing secondary probes which are not of interest and in that case such platforms may be used and only the signals associated with the probes of interest analysed. This is particularly applicable in the case of large commercially available arrays carrying an abundance of relevant probes.

Alternatively probes may be synthesized in situ onto arrays such as the Affymetrix platforms by methods known in the art.

One or more unique oligonucleotide probes may be associated with separate solid supports which together form a set of probes immobilized on multiple solid support, e.g. one or more unique probes may be immobilized on multiple beads, membranes, filters, biochips etc. which together form a set of probes, which together form modules of the kit described hereinafter. The solid support of the different modules are conveniently physically associated although the signals associated with each probe (generated as described hereinafter) must be separately determinable. Alternatively, the probes may be immobilized on discrete portions of the same solid support, e.g. each unique oligonucleotide probe, e.g. in multiple copies, may be immobilized to a distinct and discrete portion or region of a single filter or membrane, e.g. to generate an array. A combination of such techniques may also be used, e.g. several solid supports may be used which each immobilize several unique probes.

The expression "solid support" shall mean any solid material able to bind

oligonucleotides by hydrophobic, ionic or covalent bridges.

"Immobilization" as used herein refers to reversible or irreversible association of the probes to said solid support by virtue of such binding. If reversible, the probes remain associated with the solid support for a time sufficient for methods of the invention to be carried out.

Numerous solid supports suitable as immobilizing moieties according to the invention, are well known in the art and widely described in the literature and generally speaking, the solid support may be any of the well-known supports or matrices which are currently widely used or proposed for immobilization, separation etc. in chemical or biochemical procedures. Such materials include, but are not limited to, any synthetic organic polymer such as polystyrene, polyvinylchloride, polyethylene; or nitrocellulose and cellulose acetate; or tosyl activated surfaces; or glass or nylon or any surface carrying a group suited for covalent coupling of nucleic acids. The immobilizing moieties may take the form of particles, sheets, gels, filters, membranes, microfibre strips, tubes or plates, fibres or capillaries, made for example of a polymeric material e.g. agarose, cellulose, alginate, teflon, latex or polystyrene or magnetic beads. Solid supports allowing the presentation of an array, preferably in a single dimension are preferred, e.g. sheets, filters, membranes, plates or biochips.

Attachment of the nucleic acid molecules to the solid support may be performed directly or indirectly. For example if a filter is used, attachment may be performed by UV- induced crosslinking. Alternatively, attachment may be performed indirectly by the use of an attachment moiety carried on the oligonucleotide probes and/or solid support. Thus for example, a pair of affinity binding partners may be used, such as avidin, streptavidin or biotin, DNA or DNA binding protein (e.g. either the lac I repressor protein or the lac operator sequence to which it binds), antibodies (which may be mono- or polyclonal), antibody fragments or the epitopes or haptens of antibodies. In these cases, one partner of the binding pair is attached to (or is inherently part of) the solid support and the other partner is attached to (or is inherently part of) the nucleic acid molecules.

As used herein an "affinity binding pair" refers to two components which recognize and bind to one another specifically (i.e. in preference to binding to other molecules). Such binding pairs when bound together form a complex. Attachment of appropriate functional groups to the solid support may be performed by methods well known in the art, which include for example, attachment through hydroxyl, carboxyl, aldehyde or amino groups which may be provided by treating the solid support to provide suitable surface coatings. Solid supports presenting appropriate moieties for attachment of the binding partner may be produced by routine methods known in the art.

Attachment of appropriate functional groups to the oligonucleotide probes of the invention may be performed by ligation or introduced during synthesis or amplification, for example using primers carrying an appropriate moiety, such as biotin or a particular sequence for capture.

In the alternative, probes may be used without immobilization, e.g. tube based arrays may be used in which the probes are used in solution, e.g. in real time quantitative PCR.

Conveniently, the set of probes described hereinbefore is provided in kit form.

Thus viewed from a further aspect the present invention provides a kit comprising a set of oligonucleotide probes as described hereinbefore optionally immobilized on one or more solid supports.

Preferably, said probes are immobilized on a single solid support and each unique probe is attached to a different region of said solid support. However, when attached to multiple solid supports, said multiple solid supports form the modules which make up the kit. Especially preferably said solid support is a sheet, filter, membrane, plate or biochip.

Optionally the kit may also contain information relating to the signals generated by normal or diseased samples (as discussed in more detail hereinafter in relation to the use of the kits), standardizing materials, e.g. mRNA or cDNA from normal and/or diseased samples for comparative purposes, or reference probes as described before, labels for incorporation into cDNA, adapters for introducing nucleic acid sequences for amplification purposes, primers for amplification and/or appropriate enzymes, buffers and solutions. Optionally said kit may also contain a package insert describing how the method of the invention should be performed, optionally providing standard graphs, data or software for interpretation of results obtained when performing the invention.

The use of such kits to prepare a standard diagnostic gene transcript pattern as described hereinafter forms a further aspect of the invention.

The set of probes as described herein have various uses. Principally however they are used to assess the gene expression state of a test cell(s) in a sample to provide information relating to the organism from which said cell is derived. Gene expression alterations may be evident within the cell (e.g. mRNA transcripts) or in material released from the cell (e.g. microRNA or polypeptides) and thus the gene expression state of the cell may be tested by analysing either the cells or a sample containing the cells or material released from cells. The probes disclosed herein are useful in diagnosing, identifying or monitoring neurodegenerative diseases and various stages thereof in an organism.

Thus in a further aspect the invention provides the use of a set of oligonucleotide probes or a kit as described hereinbefore to determine the gene expression pattern of a cell or sample where the pattern reflects the level of gene expression of genes to which said oligonucleotide probes bind, comprising at least the steps of:

a) isolating mRNA from said cell or sample, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotide probes or a kit as defined herein; and

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce said pattern,

wherein the oligonucleotides in said set of oligonucleotides or kit are primary

oligonucleotides and said set or kit may additionally comprise secondary oligonucleotides which are not assessed in step c).

In the method described above secondary oligonucleotides may be present which are effectively ignored during the analysis. This allows large arrays containing the probes of interest to be used but only the information provided by hybridization of the sample to those probes is analysed. This also allows the generation of arrays which may be used for a variety of methods by analysis of the hybridization pattern of only select probes.

As mentioned previously, the oligonucleotide probes may act as direct labels of the target sequence (insofar as the complex between the target sequence and the probe carries a label) or may be used as primers. In the case of the former step c) may be performed by any appropriate means of detecting the hybridized entity, e.g. if the mRNA or cDNA is labelled the retention of label in a kit may be assessed. In the case of primers, those primers may be used to generate an amplification product which may be assessed. In that case in step b) said probes are hybridized to the mRNA or cDNA and used to amplify the mRNA or cDNA or a part thereof (of the size described herein for parts or preferred sizes for amplicons) and in step c) the amount of amplified product is assessed to produce the pattern.

In the case of techniques in which both primers and labelling probes are used, in the above method the primers and labelling probes are hybridized to the mRNA or cDNA in step b) and used to amplify the mRNA or cDNA or a part thereof. This amplification causes displacement of probes binding to relevant target sequences and the generation of a signal. In this case, in step c) the amount of mRNA or cDNA hybridizing to the probes is assessed by determining the presence or amount of the signal which is generated. Thus in a preferred aspect, said probes are labelling probes and pairs of primers and in step b) said labelling probes and primers are hybridized to said mRNA or cDNA and said mRNA or cDNA or a part thereof is amplified using said primers, wherein when said labelling probe binds to the target sequence it is displaced during amplification thereby generating a signal and in step c) the amount of signal generated is assessed to produce said pattern. All modes of detection of the presence or amount of binding of the probes as described herein to the target sequence are covered by the above described method and methods of the invention described hereinafter.

The mRNA and cDNA as referred to in this method, and the methods hereinafter, encompass derivatives or copies of said molecules, e.g. copies of such molecules such as those produced by amplification or the preparation of complementary strands, but which retain the identity of the mRNA sequence, i.e. would hybridize to the direct transcript (or its complementary sequence) by virtue of precise complementarity, or sequence identity, over at least a region of said molecule. It will be appreciated that complementarity will not exist over the entire region where techniques have been used which may truncate the transcript or introduce new sequences, e.g. by primer amplification. For convenience, said mRNA or cDNA is preferably amplified prior to step b). As with the oligonucleotides described herein said molecules may be modified, e.g. by using non-natural bases during synthesis providing complementarity remains. Such molecules may also carry additional moieties such as signalling or immobilizing means.

The various steps involved in the method of preparing such a pattern are described in more detail hereinafter.

As used herein "gene expression" refers to transcription of a particular gene to produce a specific mRNA product (i.e. a particular splicing product). The level of gene expression may be determined by assessing the level of transcribed mRNA molecules or cDNA molecules reverse transcribed from the mRNA molecules or products derived from those molecules, e.g. by amplification.

The "pattern" created by this technique refers to information which, for example, may be represented in tabular or graphical form and conveys information about the signal associated with two or more oligonucleotides. Preferably said pattern is expressed as an array of numbers relating to the expression level associated with each probe.

Preferably, said pattern is established using the following linear model:

y = Xb + f Equation 1 wherein, X is the matrix of gene expression data and y is the response variable, b is the regression coefficient vector and f the estimated residual vector. Although many different methods can be used to establish the relationship provided in equation 1 , especially preferably the partial Least Squares Regression (PLSR) method is used for establishing the relationship in equation 1.

The probes are thus used to generate a pattern which reflects the gene expression of a cell at the time of its isolation or a sample which may or may not contain cells but which carries expression products released by the cell. The pattern of expression is characteristic of the circumstances under which that cells finds itself and depends on the influences to which the cell has been exposed. Thus, a characteristic gene transcript pattern standard or fingerprint (standard probe pattern) for cells or samples from an individual with a

neurodegenerative disease or condition or a stage thereof may be prepared and used for comparison to transcript patterns of test cells. This has clear applications in diagnosing, monitoring or identifying whether an organism is suffering from a neurodegenerative disease or condition or a stage thereof.

As described in the Examples in more detail, the probes of the invention have various uses in discriminating between various conditions in the spectrum of early to late stage neurodegenerative diseases and conditions. Principally, the probes may be used to identify a particular stage of a disease or condition or to assess the progression (predictive and retrospective) of a disease or condition. This information may be used for various purposes, e.g. for monitoring drug efficacy, to optimize drug dosage, to assess efficacy of a therapeutic treatment (e.g. to identify drugs with therapeutic potential), to identify patients suitable for treatment or clinical trails and drug discovery based on the stage of their disease or disorder (the latter which would reduce cost of patient enrolment), but more particularly to identify the stage of a particular disease or condition and/or its progression to allow its management and treatment. The methods are particularly useful in relation to Alzheimer's disease, e.g. for drug development or discovery particularly for very early stages of the disease. Thus, the present invention is concerned with a method of identifying the stage or progression of a neurological disorder or condition. The methods may be used to identifying the underlying cause of cognitive impairment, e.g. dementia. Thus the method may be used to identify if dementia in a patient is due to Alzheimer's disease or another disorder/condition. In this case, dementia associated with the neurological disease or condition is considered a stage of said disease/condition which becomes evident only after several earlier stages of the disease/condition. As used herein, a "stage" of a neurological disease or condition refers to different stages of the neurological disorder or disease which may or may not exhibit particular physiological or metabolic changes, but do exhibit changes at the genetic level which may be detected as altered gene expression. It will be appreciated that during the course of a neurological disease or disorder (or its treatment) the expression of different transcripts may vary. Thus at different stages, altered expression may not be exhibited for particular transcripts compared to "normal" samples. However, combining information from several transcripts which exhibit altered expression at one or more stages through the course of the disease or condition can be used to provide a characteristic pattern which is indicative of a particular stage of disease or condition. The stages of a neurological disease or disorder may be identified based on cognitive or motor performance tests. For example MMSE (Folstein et al., 1975, J. Psych. Res., 12(3), p189-198) and Global CDR (Morris, 1993, Neurology, 43, p2412-2414).

The maximum score for the MMSE is 30. A score of 30 is classed as normal. Based on NHS UK http:/7www.nhs.uk/Conditions/Alzheimers-disease/Paqes/Diaqnosis.aspx

Alzheimer's disease is classified as follows:

Mild: MMSE score of between 21 and 26

Moderate: MMSE score of between 10 and 20 M

Moderately severe: MMSE score of between 10 and 14

Severe: MMSE score of less than 10

Clinical Dementia Rating Scale (CDR) is a global assessment instrument that yields global (Morris, 1993, supra) and Sum of Boxes (SOB) scores (O'Bryant et al. 2008, Arch Neurol., 65(8), p1091-1095). Based on the scores the dementia severity is staged as follows:

Sum of Boxes

Staging Category

0 Normal

Questionable cognitive

0.5-4 impairment

0.5-2.5 Questionable impairment

3.0-4.0 Very mild dementia

4.5-9.0 Mild dementia

9.5-15.5 Moderate dementia

16.0-18.0 Severe dementia These two scores (Global CDR and Sum of Boxes scores) were utilized to classify patients with clear progression and patients with no clear progressions for Prospective and

Retrospective Intra-person modeling as described in the Example.

Stages of neurological disorders or diseases having MMSE, Global CDR and/or Sum of Boxes scores as described above constitute preferred stages according to the invention.

As used herein, the "progression" of a neurological disease or condition

encompasses both predictive and retrospective progression and refers to the development of the condition or disease from one stage to the next e.g. from mild to moderate or moderate to severe. In dementias, this progression may be from pre-clinical to prodromal MCI to early dementia to severe dementia. In Alzheimer's disease for example the disease may progress from very mild, to mild, to moderate to severe. CDRs associated with these stages are in the order of 0.5, 1.0, 2.0 and 3.0 respectively. Progression includes both monitoring over several time points and a single assessment for predictive assessments.

In order to assess the stage or progression of a neurological disease or condition, a standard pattern representative of that stage, or multiple stages to assess progression retrospectively or progression profile to assess progression predictively, must be prepared. The standard pattern is prepared by determining the extent of binding of total mRNA (or cDNA or related product), from cells or released expression products from a sample of one or more organisms with a neurological disease or condition with a specific stage or progression profile, to the probes. This reflects the level of transcripts which are present which correspond to each unique probe. The amount of nucleic acid material which binds to the different probes is assessed and this information together forms the gene transcript pattern standard of said neurological disease or condition with a specific stage and/or progression profile. Each such standard pattern is characteristic of a neurological disease or condition with a specific stage or progression profile.

As referred to herein a "progression profile" refers to a stage of a neurological disease or condition with specific clinical and/or pathological characteristics indicative of the expected progression of that disease or condition, e.g. prodromal dementia or stable MCI. Thus a progression profile is predictive of a particular type of progression.

It should, however, be noted that the present invention also extends to use of the probes of the invention to diagnose or identify a neurological disease or condition (and not just a specific stage or progression profile thereof), e.g. using the Table 5 probes to identify or diagnose Alzheimer's disease. In that case, when reference is made herein to the diagnosis or identification of a specific stage or progression profile of a neurological disease or condition, this extends to diagnosis or identification of the neurological disease or condition itself in the organism under study.

In a further aspect therefore, the present invention provides a method of preparing a standard gene transcript pattern characteristic of a neurological disease or condition with a specific stage or progression profile in an organism comprising at least the steps of:

a) isolating mRNA from a blood sample (e.g. containing cells) of one or more organisms having said neurological disease or condition with a specific stage or progression profile, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit as described hereinbefore specific for said neurological disease or condition with a specific stage or progression profile in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce a characteristic pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in the sample with said neurological disease or condition with a specific stage or progression profile.

As described hereinbefore, the set of probes or kit may contain uninformative secondary probes.

For convenience, said oligonucleotides are preferably immobilized on one or more solid supports.

However, in a preferred aspect, said method is performed using primers which amplify the mRNA or cDNA or a part thereof and the amount of amplified product is assessed to produce the pattern. As described hereinbefore, both labelled probes and primers may be used in preferred aspects of the invention.

The standard pattern for various specific stages or progression profiles of neurological diseases or conditions using particular probes may be accumulated in databases and be made available to laboratories on request.

"Disease" samples and organisms or "neurological disease or condition with a specific stage or progression profile" samples and organisms as referred to herein refer to organisms (or samples from the same) with clinical or pathological evidence of a

neurological disease or condition. Such organisms are known to have, or which exhibit, the neurological disease or condition (or stage thereof) under study.

"A neurological disease or condition" refers to a disease or condition which affects neurons in the brain or spinal cord and encompasses central nervous system diseases or conditions in which neuron defects occur. Examples of neurodegenerative diseases include Parkinson's, Huntington's disease and dementias. Particular dementias of interest are Alzheimer's disease, vascular dementia, dementia with Lewy bodies and frontotemporal dementia. Dementia related to Parkinson's disease is also of interest. Neurological diseases and conditions as referred to herein also encompass mild cognitive impairment (MCI) which may have various causes. Such causes include dementias and other neurodegenerative diseases discussed above as well as conditions such as depression and bipolar disorders, such as schizophrenia, all of which are covered under neurological diseases and conditions.

Neurodegenerative diseases or conditions result in progressive degeneration and/or death of nerve cells which causes problems with movement (called ataxias), or mental functioning (called dementias). The methods described herein may be used to identify or diagnose whether an individual has a specific stage or progression or progression profile of a neurological disease or condition by developing the appropriate classification models for those conditions. In one example the method may be used to identify the underlying cause of dementia. In that case, in the methods of diagnosis and identification as described herein, said organism in step a) to be tested has a dementia of unknown origin.

"Normal" as used herein refers to organisms or samples which are used for comparative purposes. Preferably, these are "normal" in the sense that they do not exhibit any indication of, or are not believed to have, any disease or condition that would affect gene expression, particularly in respect of a neurological condition or disease for which they are to be used as the normal standard. However, it will be appreciated that different stages of a neurological disease or condition may be compared and in such cases, the "normal" sample may correspond to the earlier stage of that neurological condition or disease. Comparisons may also be made between samples from organisms with a specific neurological

condition/disease and samples from organisms with other types of neurological

conditions/disorders, e.g. samples from subjects with dementia associated with Alzheimer's disease may be compared to samples from subjects with dementia associated with other conditions/disorders. In this case the specific stage to be detected is dementia associated with Alzheimer's disease and the methods of diagnosis and identification may be used to determine whether a patient suffering from dementia has Alzheimer's disease or another neurological condition/disease leading to dementia.

As used herein a "sample" refers to any sample obtained from the organism, e.g. human or non-human animal under investigation which contains cells or material secreted from cells and includes, tissues, body fluid or body waste or in the case of prokaryotic organisms, the organism itself. "Body fluids" include blood, saliva, spinal fluid, semen, lymph. "Body waste" includes urine, expectorated matter (pulmonary patients), faeces etc. "Tissue samples" include tissue obtained by biopsy, by surgical interventions or by other means e.g. placenta. Preferably however, the samples which are examined are from areas of the body not apparently affected by the disease or condition. The cells in such samples are not disease cells, i.e. neurons, have not been in contact with such disease cells and do not originate from the site of the disease or condition. The "site of disease" is considered to be that area of the body which manifests the disease in a way which may be objectively determined, e.g. the CNS. Preferably the sample is from blood or is cerebrospinal fluid. The former is particularly preferred. Cerebrospinal fluid may be used for assessment of polypeptides or microRNA as described hereinafter. Preferably the sample from blood is whole blood or a blood product (i.e. a product derived, separated or isolated from blood), such as plasma or serum. Preferably, peripheral blood is used for diagnosis.

It will however be appreciated that the method of preparing the standard transcription pattern and other methods of the invention are also applicable for use on living parts of eukaryotic organisms such as cell lines and organ cultures and explants.

As used herein, reference to "corresponding" sample etc. refers to samples containing cells or cell products preferably from the same tissue, body fluid or body waste, (e.g. blood or blood products) and preparation method, but also includes samples containing cells or cell products from tissue, body fluid or body waste which are sufficiently similar for the purposes of preparing the standard or test pattern. When used in reference to genes "corresponding" to the probes, this refers to genes which are related by sequence (which may be complementary) to the probes although the probes may reflect different splicing products of expression.

"Assessing" as used herein refers to both quantitative and qualitative assessment which may be determined in absolute or relative terms. Any appropriate techniques for the assessment may be used. For example SOLiD™ SAGE™ systems may be used for quantification of gene expression.

The invention may be put into practice as follows.

To prepare a standard transcript pattern for a specific stage or progression profile of a neurological disease or condition, sample mRNA is extracted from the sample, e.g. cells of tissues, body fluid or body waste (e.g. from blood or blood products) according to known techniques (see for example Sambrook et. al. (1989), Molecular Cloning : A laboratory manual, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.) from an individual or organism with a specific stage or progression profile of a neurological disease or condition. Owing to the difficulties in working with RNA, the RNA is preferably reverse transcribed to form first strand cDNA. Cloning of the cDNA or selection from, or using, a cDNA library is not however necessary in this or other methods of the invention. Preferably, the complementary strands of the first strand cDNAs are synthesized, i.e. second strand cDNAs, but this will depend on which relative strands are present in the oligonucleotide probes. The RNA may however alternatively be used directly without reverse transcription and may be labelled if so required.

Preferably the cDNA strands are amplified by known amplification techniques such as the polymerase chain reaction (PCR) by the use of appropriate primers. Alternatively, the cDNA strands may be cloned with a vector, used to transform a bacteria such as E. coli which may then be grown to multiply the nucleic acid molecules. When the sequence of the cDNAs are not known, primers may be directed to regions of the nucleic acid molecules which have been introduced. Thus for example, adapters may be ligated to the cDNA molecules and primers directed to these portions for amplification of the cDNA molecules. Alternatively, in the case of eukaryotic samples, advantage may be taken of the polyA tail and cap of the RNA to prepare appropriate primers.

To produce the standard diagnostic gene transcript pattern or fingerprint for a specific stage or progression profile of a neurological disease or condition, the above described oligonucleotide probes are used to probe mRNA or cDNA of the diseased sample to produce a signal for hybridization to each particular oligonucleotide probe species, i.e. each unique probe. A standard control gene transcript pattern may also be prepared if desired using mRNA or cDNA from a normal sample. Thus, mRNA or cDNA is brought into contact with the oligonucleotide probe under appropriate conditions to allow hybridization. Alternatively, specific primer sequences for highly and moderately expressed genes can be designed and methods such as quantitative RT-PCR can be used to determine the levels of highly and moderately expressed genes, particularly the genes as described herein. Hence, a skilled practitioner may use a variety of techniques which are known in the art for determining the relative level of mRNA in a biological sample.

When multiple samples are probed, this may be performed consecutively using the same probes, e.g. on one or more solid supports, i.e. on probe kit modules, or by

simultaneously hybridizing to corresponding probes, e.g. the modules of a corresponding probe kit.

To identify when hybridization occurs and obtain an indication of the number of transcripts/cDNA molecules which become bound to the oligonucleotide probes, it is necessary to identify a signal produced when the transcripts (or related molecules) hybridize (e.g. by detection of double stranded nucleic acid molecules or detection of the number of molecules which become bound, after removing unbound molecules, e.g. by washing, or by detection of a signal generated by an amplified product).

In order to achieve a signal, either or both components which hybridize (i.e. the probe and the transcript) may carry or form a signalling means or a part thereof. This "signalling means" is any moiety capable of direct or indirect detection by the generation or presence of a signal. The signal may be any detectable physical characteristic such as conferred by radiation emission, scattering or absorption properties, magnetic properties, or other physical properties such as charge, size or binding properties of existing molecules (e.g. labels) or molecules which may be generated (e.g. gas emission etc.). Techniques are preferred which allow signal amplification, e.g. which produce multiple signal events from a single active binding site, e.g. by the catalytic action of enzymes to produce multiple detectable products.

Conveniently the signalling means may be a label which itself provides a detectable signal. Conveniently this may be achieved by the use of a radioactive or other label which may be incorporated during cDNA production, the preparation of complementary cDNA strands, during amplification of the target mRNA/cDNA or added directly to target nucleic acid molecules.

Appropriate labels are those which directly or indirectly allow detection or

measurement of the presence of the transcripts/cDNA. Such labels include for example radiolabels, chemical labels, for example chromophores or fluorophores (e.g. dyes such as fluorescein and rhodamine), or reagents of high electron density such as ferritin,

haemocyanin or colloidal gold. Alternatively, the label may be an enzyme, for example peroxidase or alkaline phosphatase, wherein the presence of the enzyme is visualized by its interaction with a suitable entity, for example a substrate. The label may also form part of a signalling pair wherein the other member of the pair is found on, or in close proximity to, the oligonucleotide probe to which the transcript/cDNA binds, for example, a fluorescent compound and a quench fluorescent substrate may be used. A label may also be provided on a different entity, such as an antibody, which recognizes a peptide moiety attached to the transcripts/cDNA, for example attached to a base used during synthesis or amplification.

A signal may be achieved by the introduction of a label before, during or after the hybridization step. Alternatively, the presence of hybridizing transcripts may be identified by other physical properties, such as their absorbance, and in which case the signalling means is the complex itself. The amount of signal associated with each oligonucleotide probe is then assessed. The assessment may be quantitative or qualitative and may be based on binding of a single transcript species (or related cDNA or other products) to each probe, or binding of multiple transcript species to multiple copies of each unique probe. It will be appreciated that quantitative results will provide further information for the transcript fingerprint of the specific stage or progression profile of the neurological disease or condition which is compiled. This data may be expressed as absolute values (in the case of macroarrays) or may be determined relative to a particular standard or reference e.g. a normal control sample.

Furthermore it will be appreciated that the standard diagnostic gene pattern transcript may be prepared using one or more disease (specific stage or progression profile of a neurological disease or condition) samples (and normal samples if used) to perform the hybridization step to obtain patterns not biased towards a particular individual's variations in gene expression.

The use of the probes to prepare standard patterns and the standard diagnostic gene transcript patterns thus produced for the purpose of identification or diagnosis or monitoring of a specific stage or progression or progression profile of a neurological disease or condition in a particular organism forms a further aspect of the invention.

Once a standard diagnostic fingerprint or pattern has been determined for a specific stage or progression profile of a neurological disease or condition using the selected oligonucleotide probes, this information can be used to identify the presence or absence of a specific stage or progression profile or the progression of a neurological disease or condition in a different test organism or individual.

To examine the gene expression pattern of a test sample, a test sample of tissue, body fluid or body waste (e.g. a blood sample containing cells), corresponding to the sample used for the preparation of the standard pattern, is obtained from a patient or the organism to be studied. A test gene transcript pattern is then prepared as described hereinbefore as for the standard pattern.

In a further aspect therefore, the present invention provides a method of preparing a test gene transcript pattern comprising at least the steps of:

a) isolating mRNA from a blood sample (e.g. containing cells) of said test organism, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit as described hereinbefore specific for a specific stage or progression profile of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce said pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in said test sample.

As described hereinbefore, the set of probes or kit may contain uninformative secondary probes.

In a preferred aspect, said method is performed using primers which amplify the mRNA or cDNA or a part thereof and the amount of amplified product is assessed to produce the pattern. As described hereinbefore, both labelled probes and primers may be used in preferred aspects of the invention.

This test pattern may then be compared to one or more standard patterns to assess whether the sample contains cells which exhibit gene expression indicative of the individual having a specific stage or progression profile of a neurological disease or condition.

Thus viewed from a further aspect the present invention provides a method of diagnosing or identifying or monitoring a specific stage or progression profile of a

neurological disease or condition in an organism, comprising the steps of:

a) isolating mRNA from a blood sample (e.g. containing cells) of said organism, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit as described hereinbefore specific for a specific stage or progression profile of a

neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation;

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce a characteristic pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in said sample; and

d) comparing said pattern to a standard diagnostic pattern prepared according to the method of the invention using a sample from an organism corresponding to the organism and sample under investigation to determine the degree of correlation indicative of the presence of a specific stage or progression profile of a neurological disease or condition in the organism under investigation.

As described hereinbefore, the set of probes or kit may contain uninformative secondary probes.

The method up to and including step c) is the preparation of a test pattern as described above.

Methods of identifying a specific progression profile that is predictive of the expected progression of a neurological disease or condition has not previously been disclosed in the art. Thus in a further aspect the present invention provides a method of diagnosing or identifying a specific progression profile of a neurological disease or condition in an organism, comprising the steps of:

a) isolating mRNA from a blood sample (e.g. containing cells) of said organism, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit comprising oligonucleotides specific for a specific progression profile of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation;

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce a characteristic pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in said sample; and

d) comparing said pattern to a standard diagnostic pattern prepared according to the method of the invention using a sample from an organism corresponding to the organism and sample under investigation and a set of oligonucleotides or a kit as defined in step b) to determine the degree of correlation indicative of the presence of a specific progression profile of a neurological disease or condition in the organism under investigation.

In step d) the standard diagnostic pattern is prepared according to methods described herein, but using a set of oligonucleotides or kit as described in step d). The invention also extends to such methods of preparing standard diagnostic patterns.

In a preferred aspect, said method is performed using primers which amplify the mRNA or cDNA or a part thereof and the amount of amplified product is assessed to produce the pattern. As described hereinbefore, both labelled probes and primers may be used in preferred aspects of the invention.

As referred to herein, "diagnosis" or "identification" refers to determination of the presence or existence of the specific stage or progression profile of a neurological disease or condition in an organism. "Monitoring" refers to repeated assessments over a period of time to assess the stage or progression of the disorder or disease over time, particularly when an individual is known to be suffering from a neurological condition or disease, for example to monitor the effects of treatment or the progression of the condition or disease, e.g. to determine the suitability of a treatment or provide a prognosis. In a preferred aspect, the patient may be monitored after or during treatment, to determine the efficacy of the treatment, e.g. by reversion to normal patterns of expression. Alternatively the monitoring may allow the optimization of drug dosage or to identify compounds suitable for treatment. The methods also allow the identification of patients suitable for clinical trails as discussed hereinbefore.

Thus in one aspect the present invention provides a method of monitoring the progression of a neurological disease or condition in an organism, comprising the steps of: a) isolating mRNA from a blood sample (e.g. containing cells) of said organism, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit as described hereinbefore specific for a specific stage of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation;

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce a characteristic pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in said sample;

d) comparing said pattern to a standard diagnostic pattern prepared according to a method of the invention using a sample from an organism corresponding to the organism and sample under investigation to determine the degree of correlation indicative of the specific stage of a neurological disease or condition in the organism under investigation; e) after a time interval, repeating steps a) to d);

f) comparing the specific stage of the disease or condition identified before and after the time interval to establish the progression of said disease or condition.

Conveniently said time interval is at least 3, 6, 12, 18, 24 or 36 months.

In a further preferred aspect the present invention provides a method of determining the efficacy of a treatment of a neurological disease or condition in an organism, comprising performing steps of a) to d) as described above, before, during, and/or after treatment of said neurological condition or disease in said organism to determine the efficacy of said treatment. The degree of correlation between the pattern generated for the samples taken before, after or during treatment and the standard pattern for a specific stage or progression profile will indicate whether there is any change in the pattern and hence the success of the treatment. Reversion to normal expression patterns (by comparison with normal standard patterns) are indicative of successful treatment. The present invention also provides a method of identifying a compound suitable for the treatment of a neurodegenerative condition or disease or a specific stage or progression profile thereof in an organism comprising the steps of:

a) identifying the stage or progression profile of said organism by a method of the invention, b) administering said compound to said organism,

c) repeating step a) after step b),

d) comparing the stages or progression profiles identified in steps a) and c) to determine if any therapeutic benefit is observed in said organism relative to a comparable organism not treated by said compound.

The presence of a specific stage or progression profile of a neurodegenerative condition or disease may be determined by determining the degree of correlation between the standard and test samples' patterns. This necessarily takes into account the range of values which are obtained for normal and diseased samples. Although this can be established by obtaining standard deviations for several representative samples binding to the probes to develop the standard, it will be appreciated that single samples may be sufficient to generate the standard pattern to identify the specific stage or progression profile if the test sample exhibits close enough correlation to that standard. Conveniently, the presence, absence, or extent of a specific stage or progression profile in a test sample can be predicted by inserting the data relating to the expression level of informative probes in test sample into the standard diagnostic probe pattern established according to equation 1.

In a preferred aspect, the neurological condition is a dementia, preferably

Alzheimer's disease. The stages of Alzheimer's disease may be divided into pre-clinical, prodromal Alzheimer's disease and dementia. As referred to herein, "prodromal"

Alzheimer's disease is the pre-dementia stage of Alzheimer's disease which is the early symptomatic, pre-dementia phase in which there is episodic memory loss of the

hippocampal type without affecting instrumental activities of daily living and biomarker evidence from CSF or imaging which supports pathological changes associated with Alzheimer's disease relative to age-matched individuals. (Dubois, et al., 2007, European Neurological Disease, p53-54). The methods may also be used to detect MCI. MCI is defined as GDS stage 2 or 3 or having a CDR of 0 to 0.5 (Petersen et al., 1999, Arch.

Neurol., 56(3); p303-308; Petersen, 201 1 , N. Engl. J. Med., 364:23, p2227-22234; Morris, 1993, Neurology, 34, p2412-2413). CDR-SOB may also be used in the assessment

(O'Bryant et al., 2008, Arch Neurol., 65(8), p1091-1095). Stable MCI as referred to herein is MCI that does not progress to dementia within 2 years. Converting MCI as referred to herein is MCI that does progress to dementia within 2 years.

In particularly preferred aspects of the invention, the stage of a neurodegenerative disease or disorder is MCI, e.g. stable MCI (which does not progress within 2 years) or converting MCI (which progresses to dementia within 2 years). Alternatively the stage may be prodromal dementia, e.g. prodromal Alzheimer's disease. These stages or their progression may be identified or monitored.

The progression profile is preferably a prodromal dementia or stable MCI. The progression profile may in some instances be the same as a stage of a disorder (where that stage has a known progression) but in other instances may provide information on whether progression to a later stage of the disease or disorder can be expected.

In particularly preferred aspects of the invention, said diagnosing or identification or monitoring of a specific stage or progression profile is carried out by comparing, in accordance with methods described hereinbefore:

(i) test patterns of organisms with MCI (or unscreened test organisms) with standard patterns from organisms with stable MCI, converting MCI, MCI , prodromal Alzheimer's disease, Alzheimer's disease and/or healthy organisms;

(ii) test patterns of organisms with a stage of dementia, e.g. Alzheimer's disease with standard patterns from organisms with various stages of dementia, e.g. Alzheimer's disease (e.g. very mild, mild, moderate or severe);

(iii) test pattern of an organism with Alzheimer's disease with standard patterns from organisms with various stages or progression profiles of Alzheimer's disease.

To provide a predictive progression comparisons are made to standard patterns from progression profiles of Alzheimer's disease. However, for retrospective determinations of Alzheimer's disease progression, two determinations are made, e.g. of the type indicated in (i) to (iii) and the results compared as a function of time.

The above tests allow the identification of the following stages: prodromal AD or stable MCI in a test individual with MCI; prodromal AD or AD in a test individual; MCI (of any form) in a test individual. The following stages may be detected which may be used to follow progression: Prodromal AD or progressed AD; very mild AD or mild AD, very mild or mild dementia, AD with clear progression or AD with no clear progression. The tests also allow the diagnosis of AD.

The following progression profiles may be detected: MCI that will convert to AD; very mild AD that will convert to mild AD; moderate AD that will convert to severe AD.

The tests not only allow the diagnosis of AD from any test sample, but in particular allow the diagnosis of dementia resulting from AD in test samples from patients with various forms of dementia including dementia from Alzheimer's disease and other dementias such as vascular dementia, dementia with Lewy bodies, frontotemporal dementia and dementia related to Parkinson's disease. As described in the Examples, the sub-sets of probes from Table 1 have preferred utilities according to the invention. Thus for example, in a preferred aspect in said diagnostic method said organism has MCI and the pattern that is generated for said organism is compared to standard patterns for stable MCI and converting MCI and said set of probes comprises at least 10 Table 2 oligonucleotides or their derived, complementary or functionally equivalent oligonucleotides. Similarly the Table 2 probes may be used to generate standard patterns for stable and converting MCI. The table below provides other preferred aspects of the invention for use in generating standard patterns and performing diagnostic methods according to the invention.

In a further preferred aspect, probes exhibiting higher significance (e.g. <0.5), i.e. the probes shown in tables with an asterisk may be used instead of the full set of probes.

Furthermore, as discussed hereinbefore, the 10 or more probes which are selected are preferably probes which are common to one or more of the Tables described herein, e.g. Tables 2 and 3 or Table 9 and 10. Core probes may be selected based on a p-value of <0.5, to which additional probes may be added from relevant Tables. Each table of probes may also form a core group of probes (e.g. Table 3), to which additional probes may be added, e.g. one or probes from Table 2, in particular those exhibiting a p-value of <0.5.

In a particularly preferred aspect, probes for which sequences are provided in the tables are preferred. Context sequences are provided for all sequences, except for Assay0555 (Table 2). The full length sequences for Assay0555 (Table 5) and Assay0397 (Table 2) are missing. Thus probes from these Tables but omitting probes from sequences relating to one or both of those Assay Nos. are preferred.

Furthermore, whilst the context sequences differ, some of the full length sequences in the tables are duplicated. Thus the full length sequences for the following pairs (and triplicates) of assays are identical:

ASSAY0128 ASSAY0797

ASSAY0381 ASSAY1093

ASSAY0142 ASSAY0885

ASSAY0207 ASSAY0802

ASSAY0745 ASSAY1094

ASSAY0771 ASSAY0772

ASSAY0476 ASSAY1095

ASSAY0002 ASSAY0098

ASSAY0535 ASSAY 1 103

ASSAY0355 ASSAY0651

ASSAY0445 ASSAY0464

ASSAY0378 ASSAY0897

ASSAY0534 ASSAY1082

ASSAY0215 ASSAY0767

ASSAY0637 ASSAY1097

ASSAY091 1 ASSAY0928

ASSAY0625 ASSAY1084

ASSAY0257 ASSAY0792

ASSAY0577 ASSAY0969

ASSAY0209 ASSAY0818

ASSAY0269 ASSAY0794

ASSAY0642 ASSAY 1 104

ASSAY0668 ASSAY0684

ASSAY0919 ASSAY1083 ASSAY0709 ASSAY 1 101

ASSAY0267 ASSAY0421

ASSAY0199 ASSAY0766; and

ASSAY0196 ASSAY0853 ASSAY1074

In a preferred aspect the 10 or more probes which are selected include only one probe from the two Assay Nos in each of the above pairs of Assay Nos, i.e. each of the probes in the 10 or more probes is from a unique sequence.

Data generated using the above mentioned methods may be analysed using various techniques from the most basic visual representation (e.g. relating to intensity) to more complex data manipulation to identify underlying patterns which reflect the interrelationship of the level of expression of each gene to which the various probes bind, which may be quantified and expressed mathematically. Conveniently, the raw data thus generated may be manipulated by the data processing and statistical methods described hereinafter, particularly normalizing and standardizing the data and fitting the data to a classification model to determine whether said test data reflects the pattern of a specific stage or progression profile of a neurodegenerative condition or disease.

The methods described herein may be used to identify, monitor or diagnose a specific stage or progression profile of a neurodegenerative condition or disease, for which the oligonucleotide probes are informative. "Informative" probes as described herein, are those which reflect genes which have altered expression in the specific stage or progression profile of the neurodegenerative condition or disease. Individual probes described herein may not be sufficiently informative for diagnostic purposes when used alone, but are informative when used as one of several probes to provide a characteristic pattern, e.g. in a set as described hereinbefore.

Thus in a further aspect the present invention provides a set of probes as described hereinbefore for use in diagnosis or identification or monitoring of a specific stage or progression profile of a neurodegenerative disease or condition.

The diagnostic method may be used alone as an alternative to other diagnostic techniques or in addition to such techniques. For example, methods of the invention may be used as an alternative or additive diagnostic measure to diagnosis using for example cognitive testing, CSF biomarkers, APOE genotyping or brain volumetric measures (Gomar et al., 201 1 , Arch. Gen Psychiatry, 68(9), p961-969) for example in the identification and/or diagnosis of specific stages or progression profiles of a neurodegenerative disease or condition. In a preferred aspect the method of the invention is used in conjunction with PET imaging, e.g. for early stage AD diagnosis. The samples to be analysed may be any sample (including normal samples) or directed to specific sample groups, e.g. samples from dementia patients, MCI patients or patients with AD.

The methods of the invention may be performed on cells from prokaryotic or eukaryotic organisms which may be any eukaryotic organisms such as human beings, other mammals and animals, birds, insects, fish and plants, and any prokaryotic organism such as a bacteria.

Preferred non-human animals on which the methods of the invention may be conducted include, but are not limited to mammals, particularly primates, domestic animals, livestock and laboratory animals. Thus preferred animals for diagnosis include mice, rats, guinea pigs, cats, dogs, pigs, cows, goats, sheep, horses. Particularly preferably a human is diagnosed, identified or monitored according to the methods above.

As described above, the sample under study may be any convenient sample which may be obtained from an organism. Preferably however, as mentioned above, the sample is obtained from a site distant to the site of disease and the cells in such samples are not disease cells, have not been in contact with such cells and do not originate from the site of the disease. In such cases, although preferably absent, the sample may contain cells which do not fulfil these criteria. However, since the probes of the invention are concerned with transcripts whose expression is altered in cells which do satisfy these criteria, the probes are specifically directed to detecting changes in transcript levels in those cells even if in the presence of other, background cells.

Whilst in a preferred aspect the methods of assessment concern the development of a gene transcript pattern from a test sample and comparison of the same to a standard pattern, the elevation or depression of expression of certain markers may also be examined by examining the products of expression and the level of those products. Thus a standard pattern in relation to the expressed product may be generated.

In such methods the levels of expression of a set of polypeptides encoded by the gene to which an oligonucleotide or a derived oligonucleotide as defined hereinbefore, binds, are analysed.

Various diagnostic methods may be used to assess the amount of polypeptides (or fragments thereof) which are present. The presence or concentration of polypeptides may be examined, for example by the use of a binding partner to said polypeptide (e.g. an antibody), which may be immobilized, to separate said polypeptide from the sample and the amount of polypeptide may then be determined. The Gene IDs disclosed in the tables may be used to determine whether antibodies to the relevant polypeptides are available.

Information on the genes may be obtained for example at www.genecards.org "Fragments" of the polypeptides refers to a domain or region of said polypeptide, e.g. an antigenic fragment, which is recognizable as being derived from said polypeptide to allow binding of a specific binding partner. Preferably such a fragment comprises a significant portion of said polypeptide and corresponds to a product of normal post-synthesis processing.

Thus in a further aspect the present invention provides a method of preparing a standard gene transcript expression pattern characteristic of a neurological disease or condition with a specific stage or progression profile in an organism comprising at least the steps of:

a) releasing target polypeptides from a sample (e.g. blood or CSF) of one or more organisms having said neurological disease or condition with a specific stage or progression profile;

b) contacting said target polypeptides with one or more binding partners, wherein each binding partner is specific to a marker polypeptide (or a fragment thereof) encoded by the gene to which an oligonucleotide (or derived sequence) as defined hereinbefore binds, to allow binding of said binding partners to said target polypeptides, wherein said marker polypeptides are specific for said neurological disease or condition with a specific stage or progression profile in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and

c) assessing the target polypeptide binding to said binding partners to produce a characteristic pattern reflecting the level of gene expression of genes which express said marker polypeptides, in the sample with said neurological disease or condition with a specific stage or progression profile.

Preferably at least 10 binding partners are used (in the above method or methods described below) or more as defined in relation to the number of oligonucleotide probes in the sets defined hereinbefore. The oligonucleotide which binds to the gene refers to an oligonucleotide probe as described hereinbefore. Preferred oligonucleotide probes or sets of probes, which bind to genes which encode marker polypeptides to which binding partners as referred to herein bind, are as described hereinbefore. Thus sets of binding partners may be used which correspond to the sets of oligonucleotide probes described herein.

As used herein "target polypeptides" refer to those polypeptides present in a sample which are to be detected and "marker polypeptides" are polypeptides which are encoded by the genes to which oligonucleotides or derived oligonucleotides as defined hereinbefore bind. The target and marker polypeptides are identical or at least have areas of high similarity, e.g. epitopic regions to allow recognition and binding of the binding partner. "Release" of the target polypeptides refers to appropriate treatment of a sample to provide the polypeptides in a form accessible for binding of the binding partners, e.g. by lysis of cells where these are present. The samples used in this case need not necessarily comprise cells as the target polypeptides may be released from cells into the surrounding tissue or fluid, and this tissue or fluid may be analysed, e.g. whole blood, serum or plasma. Preferably however the preferred samples as described herein are used, e.g. CSF or blood. "Binding partners" comprise the separate entities which together make an affinity binding pair as described above, wherein one partner of the binding pair is the target or marker polypeptide and the other partner binds specifically to that polypeptide, e.g. an antibody.

Various arrangements may be envisaged for detecting the amount of binding pairs which form. In its simplest form, a sandwich type assay e.g. an immunoassay such as an ELISA, may be used in which an antibody specific to the polypeptide and carrying a label (as described elsewhere herein) may be bound to the binding pair (e.g. the first

antibody:polypeptide pair) and the amount of label detected.

Other methods as described herein may be similarly modified for analysis of the protein product of expression rather than the gene transcript and related nucleic acid molecules.

Thus a further aspect of the invention provides a method of preparing a test gene transcript expression pattern comprising at least the steps of:

a) releasing target polypeptides from a sample (e.g. blood or CSF) of said test organism;

b) contacting said target polypeptides with one or more binding partners, wherein each binding partner is specific to a marker polypeptide (or a fragment thereof) encoded by the gene to which an oligonucleotide (or derived sequence) as defined hereinbefore binds, to allow binding of said binding partners to said target polypeptides, wherein said marker polypeptides are specific for a specific stage or progression profile of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and

c) assessing the target polypeptide binding to said binding partners to produce a characteristic pattern reflecting the level of gene expression of genes which express said marker polypeptides, in said test sample.

A yet further aspect of the invention provides a method of diagnosing or identifying or monitoring a specific stage or progression profile of a neurological disease or condition in an organism comprising the steps of:

a) releasing target polypeptides from a sample (e.g. blood or CSF) of said organism; b) contacting said target polypeptides with one or more binding partners, wherein each binding partner is specific to a marker polypeptide (or a fragment thereof) encoded by the gene to which an oligonucleotide (or derived sequence) as defined hereinbefore binds, to allow binding of said binding partners to said target polypeptides, wherein said marker polypeptides are specific for a specific stage or progression profile of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and

c) assessing the target polypeptide binding to said binding partners to produce a characteristic pattern reflecting the level of gene expression of genes which express said marker polypeptides in said sample; and

d) comparing said pattern to a standard diagnostic pattern prepared as described hereinbefore using a sample from an organism corresponding to the organism and sample under investigation to determine the degree of correlation indicative of the presence of a specific stage or progression profile of a neurological disease or condition in the organism under investigation.

MicroRNA profiling may be used to develop a pattern characteristic of a specific stage or progression profile of a neurodegenerative disease or disorder as defined above. miRNA microarrays suitable for this purpose are known in the art. In particular miRNA that regulate the genes corresponding to the probes described herein may be used to generate miRNA patterns associated with a specific stage or progression profile.

The methods of generating standard and test patterns and diagnostic techniques rely on the use of informative oligonucleotide probes to generate the gene expression data. In some cases it will be necessary to select these informative probes for a particular method, e.g. to diagnose a specific stage or progression profile of a neurological condition or disorder, from a selection of available probes, e.g. the Table 1 oligonucleotides, the Table 1 derived oligonucleotides, their complementary sequences and functionally equivalent oligonucleotides. Said derived oligonucleotides include oligonucleotides derived from the genes corresponding to the sequences provided in those tables for which gene identifiers are provided. The following methodology describes a convenient method for identifying such informative probes, or more particularly how to select a suitable sub-set of probes from the probes described herein.

Probes for the analysis of a particular stage or progression profile, may be identified in a number of ways known in the prior art, including by differential expression or by library subtraction (see for example W098/49342). As described in WO04/046382 and as described hereinafter, in view of the high information content of most transcripts, as a starting point one may also simply analyse a random sub-set of mRNA or cDNA species corresponding to the probes described herein and pick the most informative probes from that sub-set.

The following method describes the use of immobilized oligonucleotide probes (e.g. the probes of the invention) to which mRNA (or related molecules) from different samples are bound to identify which probes are the most informative to identify a specific stage or progression profile, e.g. a disease sample. Alternatively, the sub-sets described

hereinbefore may be used for the methods described herein. The method below describes how to identify sub-sets of probes from those which are disclosed herein or how to identify additional informative probes that could be used in conjunction with probes disclosed herein. The method also describes the statistical methods used for diagnosis of samples once the probes have been selected.

The immobilized probes can be derived from various unrelated or related organisms; the only requirement is that the immobilized probes should bind specifically to their homologous counterparts in test organisms. Probes can also be derived or selected from commercially available or public databases and immobilized on solid supports, or as mentioned above they can be randomly picked and isolated from a cDNA library and immobilized on a solid support.

The length of the probes immobilised on the solid support should be long enough to allow for specific binding to the target sequences. The immobilised probes can be in the form of DNA, RNA or their modified products or PNAs (peptide nucleic acids). Preferably, the probes immobilised should bind specifically to their homologous counterparts

representing highly and moderately expressed genes in test organisms. Conveniently the probes which are used are the probes described herein.

The gene expression pattern of cells in biological samples can be generated using prior art techniques such as microarray or macroarray as described below or using methods described herein. Several technologies have now been developed for monitoring the expression level of a large number of genes simultaneously in biological samples, such as, high-density oligoarrays (Lockhart et al., 1996, Nat. Biotech., 14, p1675-1680), cDNA microarrays (Schena et al, 1995, Science, 270, p467-470) and cDNA macroarrays (Maier E et al., 1994, Nucl. Acids Res., 22, p3423-3424; Bernard et al., 1996, Nucl. Acids Res., 24, p1435-1442).

In high-density oligoarrays and cDNA microarrays, hundreds and thousands of probe oligonucleotides or cDNAs, are spotted onto glass slides or nylon membranes, or synthesized on biochips. The mRNA isolated from the test and reference samples are labelled by reverse transcription with a red or green fluorescent dye, mixed, and hybridised to the microarray. After washing, the bound fluorescent dyes are detected by a laser, producing two images, one for each dye. The resulting ratio of the red and green spots on the two images provides the information about the changes in expression levels of genes in the test and reference samples. Alternatively, single channel or multiple channel microarray studies can also be performed.

The generated gene expression data needs to be preprocessed since, several factors can affect the quality and quantity of the hybridising signals. For example, variations in the quality and quantity of mRNA isolated from sample to sample, subtle variations in the efficiency of labelling target molecules during each reaction, and variations in the amount of unspecific binding between different microarrays can all contribute to noise in the acquired data set that must be corrected for prior to analysis. For example, measurements with low signal /noise ratio can be removed from the data set prior to analysis.

The data can then be transformed for stabilizing the variance in the data structure and normalized for the differences in probe intensity. Several transformation techniques have been described in the literature and a brief overview can be found in Cui, Kerr and Churchill http://www.jax.org/research/ churchill/research/ expression/Cui-T ransform.pdf. Several methods have been described for normalizing gene expression data (Richmond and Somerville, 2000, Current Opin. Plant Biol., 3, p108-1 16; Finkelstein et al., 2001 , In

"Methods of Microarray Data Analysis. Papers from CAMDA, Eds. Lin & Johnsom, Kluwer Academic, p57-68; Yang et al., 2001 , In "Optical Technologies and Informatics", Eds. Bittner, Chen, Dorsel & Dougherty, Proceedings of SPIE, 4266, p141-152; Dudoit et al, 2000, J. Am. Stat. Ass., 97, p77-87; Alter et al 2000, supra; Newton et al., 2001 , J. Comp. Biol., 8, p37- 52). Generally, a scaling factor or function is first calculated to correct the intensity effect and then used for normalising the intensities. The use of external controls has also been suggested for improved normalization.

One other major challenge encountered in large-scale gene expression analysis is that of standardization of data collected from experiments performed at different times. We have observed that gene expression data for samples acquired in the same experiment can be efficiently compared following background correction and normalization. However, the data from samples acquired in experiments performed at different times requires further standardization prior to analysis. This is because subtle differences in experimental parameters between different experiments, for example, differences in the quality and quantity of mRNA extracted at different times, differences in time used for target molecule labelling, hybridization time or exposure time, can affect the measured values. Also, factors such as the nature of the sequence of transcripts under investigation (their GC content) and their amount in relation to the each other determines how they are affected by subtle variations in the experimental processes. They determine, for example, how efficiently first strand cDNAs, corresponding to a particular transcript, are transcribed and labelled during first strand synthesis, or how efficiently the corresponding labelled target molecules bind to their complementary sequences during hybridization. Batch to batch differences in the manufacturing lots is also a major factor for variation in the generated expression data.

Failure to properly address and rectify for these influences leads to situations where the differences between the experimental series may overshadow the main information of interest contained in the gene expression data set, i.e. the differences within the combined data from the different experimental series. Hence, when required the expression data should be batch-adjusted prior to data analysis.

Monitoring the expression of a large number of genes in several samples leads to the generation of a large amount of data that is too complex to be easily interpreted. Several unsupervised and supervised multivariate data analysis techniques have already been shown to be useful in extracting meaningful biological information from these large data sets. Cluster analysis is by far the most commonly used technique for gene expression analysis, and has been performed to identify genes that are regulated in a similar manner, and or identifying new/unknown tumour classes using gene expression profiles (Eisen et al., 1998, PNAS, 95, p14863-14868, Alizadeh et al. 2000, supra, Perou et al. 2000, Nature, 406, p747- 752; Ross et al, 2000, Nature Genetics, 24(3), p227-235; Herwig et al., 1999, Genome Res., 9, p1093-1 105; Tamayo et al, 1999, Science, PNAS, 96, p2907-2912).

In the clustering method, genes are grouped into functional categories (clusters) based on their expression profile, satisfying two criteria: homogeneity - the genes in the same cluster are highly similar in expression to each other; and separation - genes in different clusters have low similarity in expression to each other.

Examples of various clustering techniques that have been used for gene expression analysis include hierarchical clustering (Eisen et al., 1998, supra; Alizadeh et al. 2000, supra; Perou et al. 2000, supra; Ross et al, 2000, supra), K-means clustering (Herwig et al., 1999, supra; Tavazoie et al, 1999, Nature Genetics, 22(3), p. 281-285), gene shaving (Hastie et al., 2000, Genome Biology, 1 (2), research 0003.1-0003.21 ), block clustering (Tibshirani et al., 1999, Tech report Univ Stanford.) Plaid model (Lazzeroni, 2002, Stat. Sinica, 12, p61-86), and self-organizing maps (Tamayo et al. 1999, supra). Also, related methods of multivariate statistical analysis, such as those using the singular value decomposition (Alter et al., 2000, PNAS, 97(18), p10101 -10106; Ross et al. 2000, supra) or multidimensional scaling can be effective at reducing the dimensions of the objects under study.

However, methods such as cluster analysis and singular value decomposition are purely exploratory and only provide a broad overview of the internal structure present in the data. They are unsupervised approaches in which the available information concerning the nature of the class under investigation is not used in the analysis. Often, the nature of the biological perturbation to which a particular sample has been subjected is known. For example, it is sometimes known whether the sample whose gene expression pattern is being analysed derives from a diseased or healthy individual. In such instances, discriminant analysis can be used for classifying samples into various groups based on their gene expression data.

In such an analysis one builds the classifier by training the data that is capable of discriminating between member and non-members of a given class. The trained classifier can then be used to predict the class of unknown samples. Examples of discrimination methods that have been described in the literature include Support Vector Machines (Brown et al, 2000, PNAS, 97, p262-267), Nearest Neighbour (Dudoit et al., 2000, supra),

Classification trees (Dudoit et al., 2000, supra), Voted classification (Dudoit et al., 2000, supra), Weighted Gene voting (Golub et al. 1999, supra), and Bayesian classification (Keller et al. 2000, Tec report Univ of Washington). Also a technique in which PLS (Partial Least Square) regression analysis is first used to reduce the dimensions in the gene expression data set followed by classification using logistic discriminant analysis and quadratic discriminant analysis (LD and QDA) has been described (Nguyen & Rocke, 2002,

Bioinformatics, 18, p39-50 and 1216-1226).

A challenge that gene expression data poses to classical discriminatory methods is that the number of genes whose expression are being analysed is very large compared to the number of samples being analysed. However in most cases only a small fraction of these genes are informative in discriminant analysis problems. Moreover, there is a danger that the noise from irrelevant genes can mask or distort the information from the informative genes. Several methods have been suggested in literature to identify and select genes that are informative in microarray studies, for example, t-statistics (Dudoit et al, 2002, J. Am. Stat. Ass., 97, p77-87), analysis of variance (Kerr et al., 2000, PNAS, 98, p8961-8965),

Neighbourhood analysis (Golub et al, 1999, supra), Ratio of between groups to within groups sum of squares (Dudoit et al., 2002, supra), Non parametric scoring (Park et al., 2002, Pacific Symposium on Biocomputing, p52-63) and Likelihood selection (Keller et al., 2000, supra). In the methods described herein the gene expression data that has been normalized and standardized is analysed by using Partial Least Squares Regression (PLSR). Although PLSR is primarily a method used for regression analysis of continuous data, it can also be utilized as a method for model building and discriminant analysis using a dummy response matrix based on a binary coding. The class assignment is based on a simple dichotomous distinction such as healthy (class 1 ) / prodromal Alzheimer's disease (class 2), or a multiple distinction based on multiple disease diagnosis such as prodromal Alzheimer's disease (class 1 ) / stable MCI (class 2) / healthy (class 3). The list of diseases for classification can be increased depending upon the samples available corresponding to other cancers or stages thereof.

PLSR applied as a classification method is referred to as PLS-DA (DA standing for Discriminant analysis). PLS-DA is an extension of the PLSR algorithm in which the Y-matrix is a dummy matrix containing n rows (corresponding to the number of samples) and K columns (corresponding to the number of classes). The Y-matrix is constructed by inserting 1 in the kt column and -1 in all the other columns if the corresponding /^'th object of X belongs to class k. By regressing Y onto X, classification of a new sample is achieved by selecting the group corresponding to the largest component of the fitted, y(x) = (y i(x), y ₂(x),..., y_k(x))- Thus, in a -1/1 response matrix, a prediction value below 0 means that the sample belongs to the class designated as -1 , while a prediction value above 0 implies that the sample belongs to the class designated as 1 .

It is usually recommended to use PLS-DA as a starting point for the classification problem due to its ability to handle collinear data, and the property of PLSR as a dimension reduction technique. Once this purpose has been satisfied, it is possible to use other methods such as Linear discriminant analysis, LDA, that has been shown to be effective in extracting further information, Indahl et al. (1999, Chem. and Intell. Lab. Syst, 49, p19-31 ). This approach is based on first decomposing the data using PLS-DA, and then using the scores vectors (instead of the original variables) as input to LDA. Further details on LDA can be found in Duda and Hart (Classification and Scene Analysis, 1973, Wiley, USA).

The next step following model building is of model validation. This step is considered to be amongst the most important aspects of multivariate analysis, and tests the "goodness" of the calibration model which has been built. In this work, a cross validation approach has been used for validation. In this approach, one or a few samples are kept out in each segment while the model is built using a full cross-validation on the basis of the remaining data. The samples left out are then used for prediction/classification. Repeating the simple cross-validation process several times holding different samples out for each cross-validation leads to a so-called double cross-validation procedure. This approach has been shown to work well with a limited amount of data, as is the case in the Examples described here. Also, since the cross validation step is repeated several times the dangers of model bias and overfitting are reduced.

Once a calibration model has been built and validated, genes exhibiting an expression pattern that is most relevant for describing the desired information in the model can be selected by techniques described in the prior art for variable selection, as mentioned elsewhere. Variable selection will help in reducing the final model complexity, provide a parsimonious model, and thus lead to a reliable model that can be used for prediction.

Moreover, use of fewer genes for the purpose of providing diagnosis will reduce the cost of the diagnostic product. In this way informative probes which would bind to the genes of relevance may be identified.

We have found that after a calibration model has been built, statistical techniques like Jackknife (Effron, 1982, The Jackknife, the Bootstrap and other resampling plans. Society for Industrial and Applied mathematics, Philadelphia, USA), based on resampling

methodology, can be efficiently used to select or confirm significant variables (informative probes). The approximate uncertainty variance of the PLS regression coefficients B can be estimated by:

M

S²B = ∑ ((B-B_m)g)²

m=1 where

S²B = estimated uncertainty variance of B;

B = the regression coefficient at the cross validated rank A using all the N objects;

B_m = the regression coefficient at the rank A using all objects except the object(s) left out in cross validation segment m; and

g = scaling coefficient (here: g=1 ).

In our approach, Jackknife has been implemented together with cross-validation. For each variable the difference between the B-coefficients B, in a cross-validated sub-model and Btot for the total model is first calculated. The sum of the squares of the differences is then calculated in all sub-models to obtain an expression of the variance of the B, estimate for a variable. The significance of the estimate of B, is calculated using the t-test. Thus, the resulting regression coefficients can be presented with uncertainty limits that correspond to 2 Standard Deviations, and from that significant variables are detected.

No further details as to the implementation or use of this step are provided here since this has been implemented in commercially available software, The Unscrambler, CAMO ASA, Norway. Also, details on variable selection using Jackknife can be found in Westad & Martens (2000, J. Near Inf. Spectr., 8, p1 17-124).

The following approach can be used to select informative probes from a gene expression data set:

a) keep out one unique sample (including its repetitions if present in the data set) per cross validation segment;

b) build a calibration model (cross validated segment) on the remaining samples using PLSR-DA;

c) select the significant genes for the model in step b) using the Jackknife criterion;

d) repeat the above 3 steps until all the unique samples in the data set are kept out once (as described in step a). For example, if 75 unique samples are present in the data set, 75 different calibration models are built resulting in a collection of 75 different sets of significant probes;

e) optionally select the most significant variables using the frequency of occurrence criterion in the generated sets of significant probes in step d). For example, a set of probes appearing in all sets (100%) are more informative than probes appearing in only 50% of the generated sets in step d).

Once the informative probes for a disease have been selected, a final model is made and validated. The two most commonly used ways of validating the model are cross- validation (CV) and test set validation. In cross-validation, the data is divided into k subsets. The model is then trained k times, each time leaving out one of the subsets from training, but using only the omitted subset to compute error criterion, RMSEP (Root Mean Square Error of Prediction). If k equals the sample size, this is called "leave-one-out" cross-validation. The idea of leaving one or a few samples out per validation segment is valid only in cases where the covariance between the various experiments is zero. Thus, one sample at-a-time approach can not be justified in situations containing replicates since keeping only one of the replicates out will introduce a systematic bias to the analysis. The correct approach in this case will be to leave out all replicates of the same samples at a time since that would satisfy assumptions of zero covariance between the CV-segments. The second approach for model validation is to use a separate test-set for validating the calibration model. This requires running a separate set of experiments to be used as a test set. This is the preferred approach given that real test data are available.

The final model is then used to identify the specific stage or progression profile of a neurological condition or disorder in test samples. For this purpose, expression data of selected informative genes is generated from test samples and then the final model is used to determine whether a sample belongs to a diseased or non-diseased class, i.e. whether the sample is from an individual with a specific stage or progression profile of a neurological condition or disorder.

Preferably a model for classification purposes is generated by using the data relating to the probes identified according to the above described method and/or the probes described hereinbefore. Such oligonucleotides may be of considerable length, e.g. if using cDNA (which is encompassed within the scope of the term "oligonucleotide"). The identification of such cDNA molecules as useful probes allows the development of shorter oligonucleotides which reflect the specificity of the cDNA molecules but are easier to manufacture and manipulate. Preferably the sample is as described previously.

The above described model may then be used to generate and analyse data of test samples and thus may be used for the diagnostic methods of the invention. In such methods the data generated from the test sample provides the gene expression data set and this is normalized and standardized as described above. This is then fitted to the calibration model described above to provide classification.

To identify genes that are expressed in high or moderate amount among the isolated population for use in methods of the invention, the information about the relative level of their transcripts in samples of interest can be generated using several prior art techniques. Both non-sequence based methods, such as differential display or RNA fingerprinting, and sequence-based methods such as microarrays or macroarrays can be used for the purpose. Alternatively, specific primer sequences for highly and moderately expressed genes can be designed and methods such as quantitative RT-PCR can be used to determine the levels of highly and moderately expressed genes. Hence, a skilled practitioner may use a variety of techniques which are known in the art for determining the relative level of mRNA in a biological sample.

Especially preferably the sample for the isolation of mRNA in the above described method is as described previously and is preferably not from the site of disease and the cells in said sample are not disease cells and have not contacted disease cells, for example the use of a peripheral blood sample. The following examples are given by way of illustration only in which the Figures referred to are as follows:

Figure 1 shows the population profile showing the probability of converted MCI (0 to 1 ) for each case (tag) demonstrating the discrimination between MCI stable and conversion. The 1 st, 2nd, 4th-1 1 th, 13th-24th, 26th-32nd, 35th, 54th and 64th cases were included in the MCI stable cohort and the other cases in the MCI conversion cohort.

Figures 2 to 9 provide the results of Permutation plots for the probes reported in tables 2, 5, 6, 7, 8, 9, 10 and 1 1 , respectively. AUC is the area under the curve and the X axis represents the number of variables selected from the corresponding Tables.

Figure 10 shows a prediction plot which illustrates classification of Alzheimer's disease related dementia samples and samples from other dementias using the Assays set forth in Table 22. The Alzheimer's disease samples (103 samples) appear on the x axis at +1 and the other dementia samples (40 samples) appear at -1. The y axis represents the predicted class membership. During prediction, if the prediction is correct, Alzheimer's disease samples should fall above zero and other dementia samples should fall below zero.

Example 1 : Identification of informative probes and their use to assess and monitor various stages and progression profiles in Alzheimer's disease, dementia and MCI

The present Example illustrates the utility of the probe sets described herein in the discrimination of various stages and progression profiles in Alzheimer's disease, dementia and MCI.

Materials and Methods

This experiment involved the analysis of gene expression patterns from a partial genome screen of 1 152 (384 assays x 3 cards) gene probes with the following study cohorts: Baseline Annual follow-u Cohorts

Stable MCI

MCI conversion

DiaGenic biobank

Progressive AD

Healthy controls Healthy controls

Healthy controls (n=30) (n=30)

Stable MCI: Subjects with stable MCI (i.e. without conversion to AD or other form of dementia) at baseline and after a minimum time period of 2 years were investigated. The study used the earliest available blood sample. At least 30 subjects were analyzed.

MCI conversion: Subjects were included that have a blood sample at the time of diagnosis with MCI and then received a diagnosis of AD at a follow-up session either 1 or 2 years post- baseline.

Alzheimer's disease: AD patients were monitored by conventional diagnostic testing and dementia graded as mild, moderate or severe AD, as appropriate. Transition through the groups, or based on an on-site clinical assessment, were considered a sign of progression. Suitable subjects were selected from the DiaGenic biobank.

Healthy controls: Healthy volunteers had at least 2 years of cognitive testing to ensure a stable healthy diagnosis.

Subject selection criteria

Subjects were selected according to the criteria stated above. Compiled clinical data

For each donor in the study, information from the DiaGenic Information Management System (DIMS) was compiled including blood sample data, RNA data and relevant clinical data. In addition clinical progression as well as the scores of clinical dementia rating (global CDR) and CDR sum of boxes (CDR-SOB) have been recorded for the longitudinal AD cohort. Summaries of the cohort demographics are presented in Tables 12 to 14.

Table 12 Selected cohort demographic data (%F, age, MMSE and global CDR)

Table 13 History of chronic illness

Table 14 Overview of the use of acetylcholinesterase inhibitor

Sample size

The cohort sample sizes are summarized in Table 15. Table 15 Sample sizes

Procedures

Apparatus and equipment

Test materials, standards and reagents

Reagents Material no./Lot no.

PAXgene™ Blood RNA Kit for manual extraction PreAnalytiX cat# 762174

RNA 6000 Nano assay kit Agilent cat# 5067-1512

RNA 6000 ladder Agilent cat# 5067-1529

High-capacity cDNA Reverse Transciptase Kit Applied Biosystems cat# 4368813, lot no. 1101092

TaqMan® Universal PCR Master Mix II (2X) with UNG Applied Biosystems cat# 4440038, lot no. 1012010

Water mol biograde 5 Prime Cat# 2500010

RNAse away Molecular BioProducts cat# 7002

Antibac 600521

Reference material RM006 ln-house reference material

Reference material RM005 (for use with BCT-1 cards) ln-house reference material

Applied Biosystems TaqMan® arrays 384-well format: Custom ordered cards:

MFC card 1 Batch no. A6709

MFC card 2 Batch no. A6707

MFC card 3 Batch no. A6727

Applied Biosystems TaqMan® arrays 4x96-well format: Custom ordered cards:

BCT-1 A5709 Blood samples

The blood samples were collected in PAXgene™ tubes (PreAnalytiX, Hombrechtikon, Switzerland) and left overnight at room temperature before storing at -80°C until use.

RNA extraction and quality control

Total RNA was extracted from the blood samples, quality controlled and subsequently stored at <-70°C prior to further processing. cDNA synthesis

2210 ng total PAXgene blood RNA was required for one cDNA synthesis for gene

expression analysis on the entire set of MFCs (3 x 384-array cards).

The cDNA syntheses were performed in one day for the primary run and in one day for the rerun samples. The cDNA was prepared with the following specifics for the present study:

The volumes of the components used to prepare the master mix for the cDNA reverse transcription for all samples including reference material is presented in

Table 16.

Table 16 Volume of components used to prepare cDNA the master mix

For each sample specific cDNA master mix, water was added to 1 .5 ml eppendorf tubes. The cDNA master mix was prepared for all samples and distributed as 130 μΙ aliquots in the tubes already containing water. Finally, RNA was added to master mix aliquots to a total volume of 260 μΙ. The final concentration of RNA in the cDNA reaction mixture was 8.5 ng/μΙ.

PCR strips of 8 wells were used for cDNA synthesis. All cDNA syntheses for the primary run and the rerun samples were prepared during the course of one day, respectively, but the cDNA syntheses were prepared in several blocks on the Tetrad thermocycler. After the cDNA synthesis, the cDNA preparations were pooled and stored at -20°C upon the addition of the PCR master mix in the qPCR step. qPCR on ViiA 7

Amplification of cDNA was the second step in the two-step real-time (RT) qPCR experiment. The MFCs were run on 2 VNA7 Dx systems from Applied Biosystems. The VNA7 instruments were qualified according to internal procedures prior to use.

MFC cards and TaqMan assays

The sample-specific PCR mix was loaded into a set of 3 MFC each comprising 384 different TaqMan assays. These assays comprised in-house assay as well as reference and known assays.

The cards were run sequentially during the primary run. For the re-run the samples were run sequentially with randomized order of cards. All 3 cards contained 7 reference assays, including beta-actin.

The TaqMan system detects PCR products using the 5' nuclease activity of Taq DNA polymerase on fluorogenic DNA probes during each extension cycle. The Taqman probe (normally 25 mer) is labelled with a fluorescent reporter dye at the 5'-end and a fluorescent quencher dye at the 3'-end. When the probe is intact, the quencher dye reduces the emission intensity of the reporter dye. If the target sequence is present the probe anneals to the target and is cleaved by the 5' nuclease activity of Taq DNA polymerase as the primer extension proceeds. As the cleavage of the probes separates the reporter dye from the quencher dye, the reporter dye fluorescence increases as a function of PCR cycle number. The greater the initial concentration of the target nucleic acid, the sooner a significant increase in fluorescence is observed.

Prepared cDNA was subjected to real-time PCR on the ViiA7 Dx systems with the following specifics for the present study:

Each aliquot (80 μΙ) of prepared cDNA reaction was used for preparation of the sample specific PCR reaction mixture to be loaded onto one MFC card. The cDNA was diluted 1/10 in the PCR reaction mixture according to Table 17. Each 8 lanes of one card were loaded with 97 μΙ PCR reaction mixture. Table 17 Volume of components used to prepare the PCR reaction mixture per MFC card

Reference material

Reference samples were run throughout the experiment at regular time. These were used to monitor technical aspects such as inter-card and inter-day variability.

Biological modeling Classification and merging

The classes and merged classes used for biological modeling are defined in Table 18 and Table 19, respectively.

Table 18 Classes

The 31 samples in L1 and L2 were from the same donor.

Table 19 Merged classes

Name Classes Samples

MCI C+S 66

Non-MCI HC+L1/L2 63

Non-AD HC+S 63

AD C+L2 61 Statistical Modeling

The data generated from the ABI Viia7 instrument was preprocessed using a single reference assay, beta-actin. Assays from each card (containing 384 assays including different reference assays), 3 cards in total, were individually normalized with the beta-actin measurement within this card. In this analysis any missing values present were filled by the mean value of that particular assay. Excluding references, gene expression data from 1 123 assays have been analyzed. The data were scaled during analysis. Partial Least Square Analysis was used for data modeling and variable selection was performed by Jackknifing. Performance results from all data are based on Leave- One- Out Cross-Validation approach (LOOCV) while the performance of models based on significant or informative assays were estimated by double Leave- One- Out Cross-Validation approach (dLOOCV) approach.

For the analysis the 5 outliers mentioned above were removed. The efficacy population thus comprises the following sample cohorts:

Table 20: Examined classes

The 31 samples in L1 and L2 were from the same donor.

1. Blood based gene expression test to detect Prodromal AD (or MCI converters or preclinical AD) in MCI population

A PLSR model was built using all 1 123 assay data derived from an effective population of 61 samples (31 stable MCI and 30 MCI converters). Performance of the model was determined by leave-one-out cross validation. 225 assays having a p-value of regression coefficient < 0.2 were identified as significant or informative (listed in Table 2). The predictive ability of the identified probes was estimated by double leave-one-out cross validation.

In addition, a preselected set of 20 assays identified as informative in independent studies (Table 3) was tested for its ability to detect Prodromal AD in an MCI population. For this purpose a PLSR model was built using these assays and 61 samples (31 stable MCI and 30 MCI converters) and prediction performance determined by LOOCV. The performance results are summarized below.

Supporting external data

A contract research organization performed an independent analysis to further support the internal findings based on data for 129 cases (Table 21 ) with a primary aim to identify a predictive signature to classify S vs. C.

Table 21 Classes with QC approved data

An artificial neural network was trained with an optimal number of assays and validated with monte-carlo cross validation re-sampling. In the cross validation procedure 80 % of the samples were used for model training and 20 % for model validation. Predictions were summarized and averaged per sample to produce an average predicted score and a standard deviation. The optimal number of assays to use in the network was determined by adding 1 by 1 assay until there was no improvement to accuracy of the classifier. This was all performed within each cross validation loop to prevent information leakage and bias to the performance. With a 10-gene panel (Table 4) the network was able to classify MCI converts from MCI stable with 88 % accuracy. The population profile with MCI conversion prediction score for each individual case is shown in Figure 1 . 2. Blood based gene expression test to detect Prodromal AD and progressed AD in a heterogeneous population

A PLSR model was built using all 1 123 assay data derived from an effective population of 124 samples (32 cognitively healthy and 31 stable MCI grouped as Non-Alzheimer samples and 30 MCI converters and 31 progressed AD grouped as AD representing both preclinical and clinical Alzheimer samples) and performance determined by leave-one-out cross validation.

302 assays listed in Table 5 , having a p-value of regression coefficient < 0.05 were identified as significant or informative. Their predictive ability was estimated by double leave- one-out cross validation.

Also, Table 3 probes were tested for their ability to detect Prodromal AD and progressed AD in a heterogeneous population. A PLSR model was built using these assays and prediction performance determined by LOOCV. The different prediction results are summarized below.

Performance All data Table 5 probes Table 3 probes

% of samples

correctly predicted Accuracy 63 % 66 % 73 %

% of AD correctly

predicted Sensitivity 67 % 66 % 67 %

% of NonAD correctly

predicted Specificity 60 % 67 % 79 % 3. Blood based gene expression test to detect patients with MCI in a heterogeneous population

A PLSR model was built using all 1 123 assay data derived from an effective population of 124 samples (and 31 stable MCI grouped and 30 MCI converters grouped as MCI samples and 32 cognitively healthy 31 progressed AD grouped as Non-MCI samples) and performance determined by leave-one-out cross validation.

266 assays listed in Table 6, having a p-value of regression coefficient < 0.2 were identified as significant or informative and predictive ability estimated by double LOOCV. The prediction results are shown below:

Performance All data Table 6 probes

% of samples correctly

predicted Accuracy 71 % 75 %

% of NonMCI correctly

predicted Sensitivity 67 % 77 %

% of MCI correctly

predicted Specificity 75 % 73 %

4. Blood based gene expression test to discriminate between different stages of Alzheimer's disease

A. Test to discriminate Prodromal AD and Progressed AD

A PLSR model was built using all 1 123 assay data derived from 61 samples comprising 30 prodromal and 31 progressed samples. Converters and progressed AD will be 2 extremes for AD, and assays able to discriminate them could be used to discriminate between different stages of Alzheimer's disease. The built in model was validated by LOOCV and prediction performance determined.

Following Jackknifing, 144 assays, listed in Table 7, having a p-value of regression coefficient < 0.05 were identified as significant or informative and their predictive ability was determined by double leave-one-out cross validation. The performance results are summarized below:

B. Test to discriminate very mild and mild dementia

Clinical samples were grouped as very mild or mild based on their Clinical dementia rating. CDR rating can be used to determine functional cognitive decline in patients with dementia. Cohort Class Samples

Samples with CDR 0.5 Very Mild 78

Samples with CDR 1.0 Mild 32

1 10

A validated PLSR model was built in using all 1 123 assay and 1 10 samples (comprising of 73 very mild and 31 mild dementia cases). Jackknifing identified 82 significant and/or informative probes, listed in Table 8. Their predictive ability was determined by double leave- one-out cross validation. The performance results are summarized below:

5. Blood based gene expression test to predict the rate of disease progression in Alzheimer's patients.

Gene expression signatures to determine the rate of disease progression in AD patients were developed using two different approaches.

The first investigated the retrospective determination of AD progression using 2 different models. The first model used the difference in gene expression for AD patients at baseline and at a follow-up visit to discriminate between donors with and without clear progression (Intra-person). The second model subsequently used the probes listed in Tables 7 and 1 1 for modeling of changes in gene expression profile from baseline to follow-up visits for donors with clear progression (Inter-person).

The second approach was a prospective approach aiming at predicting the future rate of disease progression of AD patients using the gene expression data from patients at baseline visit to discriminate between donors with and without clear progression. Based on global CDR and CDR-Sum of boxes values obtained during the first (baseline) and second follow-up visits the donors were divided into 2 groups. Of the 31 donors, 16 had clear disease progression, 12 had no clear progression. In total 4 donors were removed where one was a technical outlier and for 3 no CDR and CDR-SOB were available The 27 donors were used for further analysis, see below.

Retrospective Approach

Intra-person: Change in gene expression from baseline to follow-up

The gene expression values for each assay at baseline were subtracted from the values for corresponding assay at follow-up. The data matrix obtained was then modeled by PLSR to discriminate patients with clear and non-clear disease progression. The model identified 78 informative probes with p value of regression coefficients <0.05 listed in Table 10. The performance results are summarized below.

Probes listed in

Performance All data Table 7

% of correctly

predicted samples Accuracy 78 % 67 %

% of correctly

predicted samples with

clear progression Sensitivity 87 % 73 %

% of correctly

predicted samples with

no clear progression Specificity 67 % 58 % Inter-person: Discrimination at baseline and follow-up stages of the patients with clear disease progression

For this model, 15 donors with clear progression were modelled by PLSR to discriminate between samples at baseline and follow-up. The performance results including those obtained for identified informative assays (Table 1 1 ) and assays listed in Table 7 are presented below.

Prospective modeling

To investigate the ability to predict future rate of progression of an AD patient, a model was developed using the gene expression data from baseline samples only. Informative probes were identified and validated by double LOOCV (listed in Table 9). The predictions and performance results are summarized below.

Performance All data Table 9 probes

Table 7 probe set

% of correctly

predicted samples Accuracy 67 % 73% 67 %

% of correctly

predicted samples with

clear progression Sensitivity 73 % 73% 67 %

% of correctly

predicted samples with

no clear progression Specificity 58 % 73% 67 % The results clearly show that blood based gene expression test has the ability to identify patients where disease will progress more rapidly.

Minimum probe sets analysis

The results above show the generation of data using the sets of probes presented in the various tables. However, selection of 10 or more of those probes also yields useful results. Figures 2 to 9 show the results of Permutation plots for the probes reported in the different tables. From the probes listed in the respective tables a set of probes (X axis gives the number of probes) were randomly selected and used to model the relevant classes. The process was iterated several hundred times (to be more specific 5204 iterations in total for Table 2, 1 1718 iterations in total for Table 6, 10054 iterations for Table 5, 39970 iterations for Table 7, 161636 for Table 10, 29582 iteration for Table 9, 21 1426 iteration for Table 1 1 , 57802 iteration in total for Table 8). Performance was estimated by calculating Area Under Curve (AUC) which is sensitivity/1 -specificity.

Discussion

The ability to predict whether an MCI patient will remain stable or convert to AD within the next few years is of great value and, hence, the highest expectations were associated with the classification of stable MCI and MCI converters. The use of stable MCI for the classification is highly medical relevant considering the patients presenting with subjective memory complaints may more likely be considered a case of stable MCI than a cognitively healthy subject if they are not converting to AD.

The present example demonstrates that these indeed may be discriminated. Both internal results, as well as supporting external data, using an alternative approach to data processing and model building, demonstrates the classification of stable MCI and MCI converters.

Typically an accuracy of 77 % was obtained for internal results, with external accuracy data of 88 %.

The DiaGenic's ADtect test is a gene expression test for the diagnosis of AD. The prediction is merely a positive or a negative diagnosis, without any staging of a positive AD diagnosis. Both the ability to document a progression in AD diagnosis as well as the ability to stage the AD diagnosis are of clinical relevance. In the present example, a gene expression signature to determine the progression of AD was developed. Two different approaches were investigated. The first approach investigated the retrospective determination of AD progression using 2 different models. The first model investigated the difference in gene expression for AD patients at baseline and at a follow-up visit to discriminate between donors with and without progression. The second model subsequently used the informative subset for modeling of changes in gene expression profile from baseline to follow-up visit for donors with and without progression, respectively. Using this model subjects with clear progression were correctly predicted in over 94% of cases, demonstrating the potential for the gene signature as an AD progression marker. The second approach was a prospective approach aiming at predicting the future progression of AD patients. For the investigated model an accuracy of 73 % was obtained.

Additional modelling for diagnosing and/or staging AD, diagnosing MCI and determining the severity of dementia is also reported.

Example 2: Identification of informative probes and their use to diagnose dementia resulting from Alzheimer's disease or another form of dementia

The present Example illustrates the utility of the probe sets described herein in the discrimination of dementia from Alzheimer's disease and other dementias.

Materials and Methods

Blood samples from patients mentioned in the table below were collected in PAXgene™ tubes and left overnight at room temperature before storing at -80°C until use.

Cohort Number of patients/sample size

Dementia from Alzheimer's 103

disease

Dementia from other causes: 40

Vascular dementia 10

Dementia with Lewy bodies 10

Frontotemporal Dementia 7

Dementia related to Parkinson's 13

Disease Total RNA was extracted, quality controlled and subsequently stored at <-70°C prior to further processing. cDNAs were synthesised and amplified using relevant TaqMan assays (Table 22) present on Low density array card using the ABI 7900 RT-PCR platform. The generated gene expression data was analysed by Partial Least Square Regression Analysis and built-in model cross-validated using Leave-one-out cross validation.

The results are shown in the prediction plot in Figure 10. Alzheimer's disease samples appear on the x axis at +1 and the other dementia samples (40 samples) appear at -1. The y axis represents the predicted class membership. During prediction, if the prediction is correct, Alzheimer's disease samples should fall above zero and other dementia disease samples should fall below zero. The prediction plot using the probes of Table 22 illustrates correct prediction of almost all samples allowing classification between the different groups.

The accuracy of the results may be summarized as follows:

Accuracy: 88%

Sensitivity: 91 %

Specificity: 80%

AUC : 0.91

Table 1 : Summary of informative probes. Frequency of occurrence in sets.

(- = absent, + = present) The Assay numbers refer to specific sequences for which details are provided in the Sequence Listing.

Sequence

Number Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 22

ASSAY0001 - - - + - - - + - - -

ASSAY0002 - - - + - - - + + - -

ASSAY0003 - - - + - - - + - - -

ASSAY0006 + - - + - - - + + - -

ASSAY0007 - - - - - - - - + - -

ASSAY0010 - - - + - - - - - - -

ASSAY001 1 - - - + + + + - - - -

ASSAY0012 + - - - + + - - - - -

ASSAY0013 - - - + - - - + + - -

ASSAY0014 - - - - + - - - - - -

ASSAY0015 + - - - - - - - + - - ASSAY0017 + - - + - - - + - - -

ASSAY0018 - - - - - - - + - - -

ASSAY0020 - - - - + - - - - - -

ASSAY0022 - - - - + + + + - - -

ASSAY0024 - - - - - - - + - + -

ASSAY0027 + - - + - - - + - - -

ASSAY0031 - - - - - - - + - - -

ASSAY0032 + - - - + - - - - - -

ASSAY0036 - - - - - - - + - - -

ASSAY0037 + - - - - - - - - + -

ASSAY0038 - - - - - + - - - + -

ASSAY0039 - - - - - - - - - + -

ASSAY0040 + - - + - - - + - - -

ASSAY0041 - - - - - + - + - - -

ASSAY0044 + - - + - - - - - - -

ASSAY0045 - - - + - - - - - - -

ASSAY0046 + - - + - - - - - - -

ASSAY0047 - - - + + - + + - - -

ASSAY0048 - - - + - - - - - - -

ASSAY0049 - - - - - - - + - - -

ASSAY0050 - - - - - - - + - - -

ASSAY0051 - - - - + - + - - - -

ASSAY0052 - - - - - + + - - + -

ASSAY0053 + - - - - - - + + - -

ASSAY0054 - - - - + - - + - - -

ASSAY0055 - - - - - - - + - - -

ASSAY0056 - - - + - - - - - - -

ASSAY0057 - - - - + + + + - - -

ASSAY0060 - - - + - - - - - - -

ASSAY0061 - - - - - - - + - - -

ASSAY0062 - - - + - - + - - - -

ASSAY0063 + - - + - - - - - - -

ASSAY0065 + - - + - - - + - - -

ASSAY0066 - - - - - - - - - + -

ASSAY0067 - - - + - - - - - - -

ASSAY0069 + - - - - - - - - - -

ASSAY0070 - - - - + - - + - + -

ASSAY0072 - - - - + - - - - - -

ASSAY0074 - - - + - - - - - - -

ASSAY0077 - - - - - - - - + + -

ASSAY0080 - - - - - - - + - - -

ASSAY0081 - - - - - - - - + - -

ASSAY0082 - - - - + + + - - - -

ASSAY0084 + - - + - - - - - - -

ASSAY0085 + - - + - - - + - - -

ASSAY0086 - - - + - - - - - - -

ASSAY0087 + - - - - - - - - - -

ASSAY0088 + - - - - - - - - - - ASSAY0089 - - - + + - - + - - -

ASSAY0092 - - - + - - - - - - -

ASSAY0093 + - - - + + - + - - -

ASSAY0096 - - - - + + - + - - -

ASSAY0097 - - - - - - - + - - -

ASSAY0098 - - - + - - - + + + -

ASSAY0099 - - - - - + - - - + -

ASSAY0103 + - - + - - - - - - -

ASSAY0104 - - - - - - - - - + -

ASSAY0107 - - - + - - - - - - -

ASSAY0108 - - - - - - - + - - -

ASSAY01 10 - - - - + - - - - - -

ASSAY01 12 + - - + - - - + - - -

ASSAY01 13 - - - - + + + - - - -

ASSAY01 14 - - - + + + - - - - -

ASSAY01 15 - - - - - - - + - - -

ASSAY01 16 + - - - - - - - - - -

ASSAY01 17 + - - + - - - - - - -

ASSAY01 18 - - - - - - - - + - -

ASSAY01 19 - - - + - - - + + - -

ASSAY0120 + - - + - - - + - - -

ASSAY0122 + - - - - + - - - - -

ASSAY0123 - - - - + - - - - - -

ASSAY0124 - - - + - - - - - - -

ASSAY0126 + - - + + - - - - + -

ASSAY0127 - - - - - - - + - - -

ASSAY0128 + - - + + + - - - - -

ASSAY0129 - - - + - - - - - - -

ASSAY0132 - - - - + - - + - - -

ASSAY0133 - - - - - - - + + - -

ASSAY0135 - - - - + + - - - - -

ASSAY0136 - - - + - - - + - - -

ASSAY0137 - - - - + - + + - - +

ASSAY0138 + - - - - - - - - - -

ASSAY0139 - - - - + - - - - - -

ASSAY0140 - - - - + + - - - + -

ASSAY0141 + - + + - - - - - - -

ASSAY0142 - - - + - - - - - - -

ASSAY0144 - - - - + - - - - - -

ASSAY0145 - - - - - - - + - - -

ASSAY0146 - - - - - - - - - - +

ASSAY0147 + - - + - - - - - - -

ASSAY0148 - - - - + + - - - - -

ASSAY0149 - - - + - - - - - - -

ASSAY0150 + - - + - - + + - - -

ASSAY0151 - - - + - - - - - - -

ASSAY0152 - - - + - - - - - - -

ASSAY0153 + - - - - - - - - - - ASSAY0154 - - - + - - - + - - -

ASSAY0155 - - - + - - - - - - -

ASSAY0156 + - - + - - - + - - -

ASSAY0157 + - - - - - - + - - -

ASSAY0158 + - - + - - - + - - -

ASSAY0159 - - - - - - - - - + -

ASSAY0160 + - - + - - - - - - -

ASSAY0161 - - - - + - - - - - -

ASSAY0162 - - - - - - - + + + -

ASSAY0163 - - - - + - - + - - -

ASSAY0164 - - - + - - - - - + -

ASSAY0165 + - - + - - - - - + -

ASSAY0166 - - - - - - - + - - -

ASSAY0168 - - - + - - - - - - -

ASSAY0169 - - - - - - - + - - -

ASSAY0170 - - - - - - - + - - -

ASSAY0171 - - - + - - - - - - -

ASSAY0172 - - - - - - + - + - -

ASSAY0174 - - - + - - - - - + -

ASSAY0176 - - - + - - - - - + -

ASSAY0178 + - - + + - - - - - -

ASSAY0179 - - - - + - - - - - -

ASSAY0180 - - - + - - - + - - -

ASSAY0181 - - - - + + - - - - -

ASSAY0182 - - - - + - - + - - -

ASSAY0183 + - - + - - - + - - -

ASSAY0184 - - - - + + - - - - -

ASSAY0185 - - - - - - + - - - -

ASSAY0186 - - - - - - - - + - -

ASSAY0187 - - - - - - + - - - -

ASSAY0188 - - - - - - - - - - +

ASSAY0189 - - - - - + - - - - -

ASSAY0190 - - - - + - - + - - -

ASSAY0191 - + - - - - - + - - -

ASSAY0193 - - - - + - - - - - -

ASSAY0194 - + - + - - - + - - -

ASSAY0195 + - - - - - - - - - -

ASSAY0196 - + - - - - - - - - -

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ASSAY0809 - - - + - - - - - - -

ASSAY0810 - - - - + + - - - - -

ASSAY081 1 - - - + - - - - - - -

ASSAY0814 + - - - + + + - - - -

ASSAY0817 + - - - - - - - - - -

ASSAY0818 - - - - - + - + - - -

ASSAY0819 + - - - + + - - - - -

ASSAY0820 - - - + - + + + - + -

ASSAY0821 - - - + - - - + - - -

ASSAY0822 - - - + - - - + - - -

ASSAY0826 - - - + + - + - - - -

ASSAY0827 - - - - + + - - - + -

ASSAY0831 - - - - + - - - - - -

ASSAY0833 + - - + - - - - - - -

ASSAY0834 - - - - + + - - - - -

ASSAY0835 - - - + - - - - - + -

ASSAY0836 - - - - + + + - - + -

ASSAY0838 + - - + - - - - - - -

ASSAY0841 + - - - - - - - - - -

ASSAY0842 + - - + - - - + - - -

ASSAY0843 - - - + - - - + - - -

ASSAY0844 - - - - + + + + - - -

ASSAY0846 - - - - + - - - - - -

ASSAY0847 + - - - - - - - - - -

ASSAY0850 - - - + - - - - - - -

ASSAY0853 + - - - - - - - - - -

ASSAY0854 - - - - + + - - - - -

ASSAY0856 - - - - + + + - - + -

ASSAY0857 - - - - + - - - - - -

ASSAY0858 - - - - + + - - - - -

ASSAY0859 - - - + - - - - - - -

ASSAY0861 + - - - + - - - - - -

ASSAY0862 - - - + - - - + - - -

ASSAY0863 - - - + - - - - - - -

ASSAY0865 - - - - + - - - - - -

ASSAY0866 - - - - - - - + - - - ASSAY0867 - - - + - - - - - - -

ASSAY0869 - - - - - - - - - + -

ASSAY0871 - - - - + + + - - - -

ASSAY0874 - - - - - - - + + - -

ASSAY0876 - - - + + - - + - - -

ASSAY0878 + - + - - - - - - - -

ASSAY0879 - - - + - - - - - - -

ASSAY0882 - - - - + - - + - - -

ASSAY0883 - - - + - - - - - - -

ASSAY0885 - - - - - - - + - - -

ASSAY0886 + - - + + - - + - + -

ASSAY0887 - - - - - - - + - - -

ASSAY0888 - - - - + + + - - - -

ASSAY0893 - - - - + - - - - - -

ASSAY0894 - - - - + - - - - - -

ASSAY0895 - - - - - - - + - - -

ASSAY0897 - - - + - - - - - - -

ASSAY0899 - - - - - - - + - + -

ASSAY0900 + - - - + + - - - + -

ASSAY0903 + - - - - - - - - - -

ASSAY0904 + - - + - - - - - + -

ASSAY0906 - - + - - - - - - - -

ASSAY0907 - - - + - - - - - - -

ASSAY0910 + - - - - - - - - - -

ASSAY091 1 - - - + - - - - - - -

ASSAY0912 - - - - - - - + + + -

ASSAY0913 - - - + - - - - - - -

ASSAY0914 - - - + + - + - - - -

ASSAY0916 - - - - + + + - - - -

ASSAY0917 + - - - - - - - - - -

ASSAY0919 - - - + - - - + - + -

ASSAY0921 - - - - - - - + - - -

ASSAY0922 + - - + - - - + - - -

ASSAY0923 - - - - + + - - - + -

ASSAY0924 - - - - + - - - - - -

ASSAY0925 - - - - + - + - - - -

ASSAY0927 - - - - - - - + - - -

ASSAY0928 + - - - - - - - - - -

ASSAY0929 - - - - + - - - - - -

ASSAY0931 - - - + - - - - - - -

ASSAY0933 - - - - + - - - - - -

ASSAY0934 - - - - + - - - - - -

ASSAY0935 - - - + - - - + + - -

ASSAY0936 - - - - + - - - - - -

ASSAY0938 + - - - - - - - - - -

ASSAY0939 - - - + - - - - - - -

ASSAY0941 - - - - + - + + - - -

ASSAY0943 + - - - - - - - - - - ASSAY0944 - - - + + - - - - - -

ASSAY0947 - - - + - - + + - - -

ASSAY0948 + - - + - - - - - - -

ASSAY0950 + - - + + - - - - - -

ASSAY0951 - - - - + - - - - - -

ASSAY0953 + - - - - - - - - - -

ASSAY0957 - - - + - - - + - - -

ASSAY0959 - - - + - + - - - - -

ASSAY0960 + - - - - - - + + - -

ASSAY0962 - - - + + + - + + + -

ASSAY0964 - - - + - - - - - - -

ASSAY0966 - - - + - + - - - + -

ASSAY0968 - - - + - - - - - - -

ASSAY0969 - - - + - - - + - - -

ASSAY0970 - - - - + - - - - - -

ASSAY0971 + - - + - - - + - - -

ASSAY0976 + - - - - - + - - - -

ASSAY0978 + - - + - - - - - - -

ASSAY0980 - - - - + - - - - - -

ASSAY0982 - - - - + - - - - - -

ASSAY0983 + - - - - - - - - - -

ASSAY0985 + - - - - - - - - - -

ASSAY0986 - - - - - - - + - - -

ASSAY0987 - - - - - - - + - - -

ASSAY0988 - - - - - + - - - - -

ASSAY0990 - - - + - - - - - - -

ASSAY0992 + - - - - - - - + - -

ASSAY0994 - - - + - - - - - - -

ASSAY0996 + - - - + + - - - - -

ASSAY0997 - - - - - - - + - - -

ASSAY0998 + - - - + - - - - - -

ASSAY 1000 + - - - + + - - + - -

ASSAY 1001 - - - - + - - - - - -

ASSAY 1002 - - - - - - - + - - -

ASSAY 1004 - - - - + - - + - - -

ASSAY 1006 + - - + - - - - - - -

ASSAY 1007 - - - - - - - + - - -

ASSAY1010 + - - - + - - - - - -

ASSAY101 1 + - - - - - - - - - -

ASSAY1012 + - - - - - - - - - -

ASSAY1014 - - - - - - + - - - -

ASSAY1017 + - + - - - - - - - -

ASSAY1018 + - - - - - - - - - -

ASSAY1019 - - - - - - - + - - -

ASSAY 1022 - - - + - - - - - - -

ASSAY 1023 - - - + - - + - - - -

ASSAY 1024 + - - + - - - - - + -

ASSAY 1025 + - + + + - - - - - - ASSAY 1026 + - - + + - + + - - -

ASSAY 1029 - - - + - - - - - - -

ASSAY 1030 - - - - + - - - - - -

ASSAY 1033 + - - - - - - - - - -

ASSAY 1035 - - - - - - + - - + -

ASSAY 1036 - - - + + - - - - - -

ASSAY 1037 + - - - - - - + - - -

ASSAY 1039 - - - + - - - + + + -

ASSAY 1040 + - - - - - - - - - -

ASSAY 1041 + - - - - - - - - - -

ASSAY 1042 - - - - + - - + - - -

ASSAY 1044 + - - - - - - - - - -

ASSAY 1045 - - - + - - - - - - -

ASSAY 1046 - - - + - - - - - - -

ASSAY 1047 + - - - - - - - + - -

ASSAY 1048 - - - - + - - - - - -

ASSAY 1051 - - - - - - - + - - -

ASSAY 1052 - - - + - - - - - - -

ASSAY 1053 - - - + - - - - - - -

ASSAY 1055 - - - - - - - - - + -

ASSAY 1056 + - - - + - - - - - -

ASSAY 1057 - - - + - - - - - - -

ASSAY 1058 + - - - - - - + - - -

ASSAY 1059 + - - + - - - + - - -

ASSAY 1061 - - - + - - - + - - -

ASSAY 1063 - - - + - - - - - - -

ASSAY 1064 - - - - + - - + - - -

ASSAY 1065 - - + - - - - - - - -

ASSAY 1066 - - - - - + - - - - -

ASSAY 1071 - - - - - + - - - - -

ASSAY 1074 - - - + - - - - - - -

ASSAY 1075 + - - - - - - - - - -

ASSAY 1077 - - - - - - - - + - -

ASSAY 1078 - - - + - - - + - - -

ASSAY 1079 + - - - - - - - - + -

ASSAY 1081 + - - - - - - - + - -

ASSAY 1082 - - - + - - - - - - -

ASSAY 1083 - - - - + - - - - - -

ASSAY 1084 - - - + + - - + - + -

ASSAY 1086 + - - - - - - - - - -

ASSAY 1087 - - - - - + - - - - -

ASSAY 1088 + - - + + - - - - - -

ASSAY 1090 - - - + - - - - - - -

ASSAY 1093 - - - + - - - + + - -

ASSAY 1094 + - - + - - - - - - -

ASSAY 1095 + - - - - + - - - - -

ASSAY 1096 - - - + + - - - - - -

ASSAY 1097 - - - + - - - + - - - ASSAY 1099 + - - - - - - - - + -

ASSAY 1 100 - - - - + - - - - - -

ASSAY1 101 - - + + + - - - - - -

ASSAY 1 102 + - - + - - - - - - -

ASSAY 1 103 + - - - - - - + - - -

ASSAY 1 104 + - - - + - - - - + -

Table 2: Informative probes for Stable MCI versus Converting MCI

Assays with p values <0.05 are marked with an asterisk.

Sequence No.

ADP-dependent

ASSAY0084

Hs00229849 ml ADPGK glucokinase GCATTGTCCATCAGGTCTTTCCCGC anterior pharynx

ASSAY0085* defective 1 homolog

Hs00229911 ml APH1 B B (C. elegans) TCATCGCCGGAGCTTTCTTCTGGTT

ASSAY0087 Hs00230261 ml CD99L2 CD99 molecule-like 2 GCATTCAGCAGGGTCTCAACGCAGA

TM2 domain

ASSAY0088

Hs00230572 ml TM2D2 containing 2 GTTGTCTCAAGTTCGGCGGTCAGGC low density

ASSAY0093* lipoprotein receptor-

Hs00233856 ml LRP1 related protein 1 CCCCTGAGATTTGTCCACAGAGTAA caspase 6,

ASSAY0103 apoptosis-related

Hs00154250 ml CASP6 cysteine peptidase GTGTTACTCTGTTGCAGAAGGATAT epoxide hydrolase 2,

ASSAY01 12*

Hs00157403 ml EPHX2 cytoplasmic ACGTGACAGTAAAGCCCAGGGTCCG interferon regulatory

ASSAY01 16

Hs001581 13 ml IRF5 factor 5 CCGCAGACAGACCCCTCTGCCATGA interferon regulatory

ASSAY01 17*

Hs001581 14 ml IRF5 factor 5 ACACCATCTTCAAGGCCTGGGCCAA

ASSAY0120 nardilysin (N-arginine

Hs00159668 ml NRD1 dibasic convertase) TGTCACAAGCACAGAATCTATGGAT phospholipase D1 ,

ASSAY0122 phosphatidylcholine-

Hs001601 18 ml PLD1 specific CTT AAACG AAAAG C AC AAC AAG GAG sterol O-

ASSAY0126*

Hs00162077 ml SOAT1 acyltransferase 1 CCATCTTGCCAGGTGTGCTGATTCT

Bruton

ASSAY0128 agammaglobulinemia

Hs00163761 ml BTK tyrosine kinase GTCAGGACTGAGCACACAGGTGAAC cellular repressor of

ASSAY0138 E1A-stimulated

Hs00171585 ml CREG1 genes 1 TGAGCAACCTGCAGGAGAATCCATA

ASSAY0141 Hs00173570 ml GRN granulin GTCGGACGCAGGCAGACCATGTGGA angiotensin I

converting enzyme

ASSAY0147*

(peptidyl-dipeptidase

Hs00174179 ml ACE A) 1 AAG GACTTCCG G ATCAAGCAGTG CA

ASSAY0150* Hs00174705 ml CD163 CD163 molecule ACCTGCTCAGCCCACAGGGAACCCA

ASSAY0153 Hs00175195 ml CTSG cathepsin G GCTGGGGAAG C AAT AT AAATG TC AC

ASSAY0156 Hs00175573 ml AQP9 aquaporin 9 CATCTTGATTGTCCTTGGATGTGGC

ASSAY0157 Hs00175591 ml PRNP prion protein CACGACCGAGGCAGAGCAGTCATTA inositol 1 ,4,5-

ASSAY0158 trisphosphate 3-

Hs00176666 ml ITPKB kinase B GCAAGATGGGAATCAGGACCTACCT protein kinase C,

ASSAY0160*

Hs00176973 ml PRKCA alpha GAACCACAAGCAGTATTCTATGCGG serine/threonine

ASSAY0165

Hs00177790 ml STK17B kinase 17b TGATATTGGAATATGCTGCAGGTGG nuclear receptor

ASSAY0178

Hs00186661 ml NCOA1 coactivator 1 CACCTCAGCCACCCCTGAATGCTCA

BCL2-associated

ASSAY0183

Hs00188713 ml BAG 3 athanogene 3 GGGCCCCAAGGAGACTCCATCCTCT

ASSAY0195 Hs00165445 ml PEPD peptidase D GAGTTGGAAAGCCTCTTCGAGCACT tumor necrosis factor

ASSAY0198 (TNF superfamily,

Hs00174128 ml TNF member 2) TAGCCCATGTTGTAGCAAACCCTCA

glycogen synthase

ASSAY0553

Hs00275656 ml GSK3B kinase 3 beta AGAAATAATCAAGGTCCTGGGAACT signal peptide

ASSAY0566

Hs00293370 ml SPPL3 peptidase 3 TATTTAAAGGGCGACCTCCGGCGGA spectrin repeat

ASSAY0576 containing, nuclear

Hs00326979 ml SYNE1 envelope 1 CAAGCTCGAGGCTCTATTATCAGTC folliculin interacting

ASSAY0580

Hs00332198 s1 FNIP2 protein 2 ACTTTCCCTCATTCACCACCTTCCA chemokine (C-C

ASSAY0584*

Hs00356601 ml CCR2 motif) receptor 2 GCCACAAGCTGAACAGAGAAAGTGG nuclear transcription

ASSAY0587

Hs00360266 g1 NFYC factor Y, gamma GATGGACAGCAGCTCTACCAGATCC cysteine-rich with

ASSAY0588

Hs00360923 g1 CRELD2 EGF-like domains 2 TCCAAGTACGAGTCCAGCGAGATTC non-protein coding

ASSAY0598*

Hs00364877 ml NCRNA00219 RNA 219 AAAGGTGACCTGAAGGATGTCCTTG chemokine (C-X3-C

ASSAY0600

Hs00365842 ml CX3CR1 motif) receptor 1 GGCAGTCCACGCCAGGCCTTCACCA

ArfGAP with GTPase

domain, ankyrin

repeat and PH

domain 4; ArfGAP

with GTPase

domain, ankyrin

repeat and PH

domain 7; ArfGAP

ASSAY0607

with GTPase

domain, ankyrin

repeat and PH

domain 6; ArfGAP

AGAP4; with GTPase

AGAP7; domain, ankyrin

AGAP6; repeat and PH

Hs00370295 ml AGAP8 domain 8 CGGGAGATGCCTGAAGCTTTGGAGT

GRB2-associated

ASSAY0614

Hs00373045 ml GAB2 binding protein 2 GAGAGCACAGACTCCCTGAGAAATG coiled-coil domain

ASSAY0623

Hs00376384 ml CCDC52 containing 52 G CT AC AC AG G C AAG ACTTC AG C AG T

PQ loop repeat

ASSAY0634*

Hs00379889 ml PQLC3 containing 3 GACCTGGCCATGAATCTATGTACTT prolyl-tRNA

synthetase 2,

ASSAY0638

mitochondrial

Hs00384448 ml PARS2 (putative) GGCTGGGATTGCGGTGCCTGTGCTT

5-nucleotidase

ASSAY0642

Hs00385559 ml NT5DC1 domain containing 1 TTTCCGGACACTCGAGAATGATGAG microsomal

ASSAY0647 glutathione S-

Hs00388932 ml MGST3 transferase 3 TTACCACCCGCGTATAGCTTCTGGC

SEC16 homolog A

ASSAY0648*

Hs00389570 ml SEC16A (S. cerevisiae) AACCTAAGAAGGGTGAATCCTGGTT

Smg-6 homolog,

nonsense mediated

ASSAY0651 *

mRNA decay factor

Hs00391737 ml SMG6 (C. elegans) ACGCAAGACAGTAAAATATGCCTTG leukocyte specific

ASSAY0655

Hs00394683 ml LST1 transcript 1 AGGCCACAAGCTCTGGATGAGGAAC

ASSAY0656* Hs00395045 ml STMN3 stathmin-like 3 CCAGTACGGGGACATGGAGGTGAAG phosphodiesterase

ASSAY0662

Hs00405478 ml PDE8B 8B GAAGCAGTGTGCAGGTCGATCCGGG

Table 3: Informative sub-set of probes for Stable MCI versus Converting MCI

Sequence No.

(DiaGenic Gene Context Sequence (Oligonucleotide Assay ID) Assay ID Symbol Gene name sequence)

growth factor receptor-

ASSAY0191 Hs00157817 ml GRB2 bound protein 2 GGGGGGACATCCTCAAGG I I I I GAA cytochrome b-245, alpha

ASSAY0194 Hs00164370 ml CYBA polypeptide GGCCTGATCCTCATCACCGGGGGCA interleukin 2 receptor,

ASSAY0196 Hs00168402 ml IL2RB beta GGGCCATGGCTGAAGAAGGTCCTGA

S100 calcium binding

ASSAY0197 Hs00170953 ml S100A6 protein A6 CCCTACCGCTCCAAGCCCAGCCCTC

ASSAY0202 Hs00182698 ml SKAP2 src kinase associated CCTCTGATGGAGCCCAGTTTCCTCC phosphoprotein 2

granzyme A (granzyme 1 ,

cytotoxic T-lymphocyte- associated serine

ASSAY0207 Hs00196206 ml GZMA esterase 3) CCTGCTAATTCCTGAAGATGTCTGT

RNA binding motif protein

ASSAY0215 Hs00208212 ml RBM19 19 ACGAGCCACTAAGCCAGCCGTGACA transmembrane protein

ASSAY0221 Hs00215267 ml TMEM127 127 CCCGGACCTGCTGAAAGATTTCTGC membrane-associated

ASSAY0222 Hs00215631 ml MARCH 1 ring finger (C3HC4) 1 AGGACATCTGCAGAATCTGTCACTG

ASSAY0226 Hs00220138 ml LXN latexin AC AAG CC AG C ATG G AG G AT ATTCC A

DENN/MADD domain

ASSAY0228 Hs00227687 ml DENND2D containing 2D TGGAAGAGGTCCTGCTGGTCAATCT

ASSAY0236 Hs00266763 ml GSPT1 G1 to S phase transition 1 CCGTGCGGCACCTGTGGAATCCTCT

ASSAY0243 Hs00292065 ml SYTL3 synaptotagmin-like 3 GTCACCACCAGGAAGGTCAGTGCAC dynein heavy chain

ASSAY0246 Hs00330168 ml DNHD1 domain 1 GGGCGCTGGAGTCAAGTGACTCTAA golgin A8 family, member

GOLGA8B; B;golgin A8 family,

ASSAY0251 Hs00367259 ml GOLGA8A member A AGAAGCCGGATGGGTTCTCGAGCCG

ASSAY0256 Hs00385050 ml RNF166 ring finger protein 166 GCGGCCACACGTTCTGCGGGGAGTG microtubule-associated

ASSAY0262 Hs00430193 ml MAP1 S protein 1 S GGAGCTCGAAAGAGGCATCCGGTCT

ASSAY0275 Hs01005146 g1 LOC651250 hypothetical LOC651250 AG C AAG TTCAGAGTTGGATGGTCTA

ASSAY0277 Hs01028786 s1 ANKRD58 ankyrin repeat domain 58 TCAGCCTCTGACAACCTCCTCCTGA

ASSAY0278 Hs01092416 s1 N/A N/A GTGTGAAGATCCAGCCTGATGCCCA

Table 4: 10 genes used for external analysis (stable MCI vs converter MCI)

Sequence No.

(DiaGenic Gene Context Sequence (Oligonucleotide Assay ID) Assay ID Symbol Gene name sequence)

ASSAY0141 Hs00173570 ml GRN granulin GTCGGACGCAGGCAGACCATGTGGA

ASSAY0460 mitochondrial translational

Hs00759012 s1 MTRF1 L release factor 1 -like CGGACTAAGGATGCGGTCCCGGGTT myeloid differentiation

ASSAY1025 primary response gene

Hs00182082 ml MYD88 (88) CCCAGCATTGAGGAGGATTGCCAAA protein tyrosine

ASSAY1017 phosphatase, receptor

Hs00894734 ml PTPRC type, C GCTTTTAATACCACAGGTGTTTCAT interleukin 23, alpha

ASSAY0759

Hs00900829 g1 IL23A subunit p19 CCTCAGCCAACTCCTGCAGCCTGAG

ASSAY1 101 mitochondrial GTPase 1

Hs00536591 g1 MTG1 homolog (S. cerevisiae) CCGAAAAGAGAACCTGGAGTACTGT degenerative

ASSAY0878 spermatocyte homolog 2,

lipid desaturase

Hs01380343 ml DEGS2 (Drosophila) CTACAACCTGCCGCTGGTGCGGAAG

ASSAY1065 NIMA (never in mitosis

Hs00205221 ml NEK6 gene a)-related kinase 6 CCTGACCCACAGAGGCATCCCAACA ASSAY0906 Hs01904238 g1 N/A N/A GGACCACCAGCCCCAGTGACAGAAC

ASSAY0758 ribosomal protein L32

Hs00898410 g1 RPL32P3 pseudogene 3 GCTGGCAGGCACCATGTCGTCCTGT

Table 5: Informative probes for Non-AD versus AD (All probes have p-value <0.5)

Sequence No. Context Sequence (Oligonucleotide (DiaGenic Assay ID Gene Gene name Sequence)

probe ID) Symbol

ASSAY0001 Hs00152932 ml TLR2 toll-like receptor 2 TCAACTGGTAGTTGTGGGTTGAAGC membrane metallo-

ASSAY0002

HsOO-153510 ml MME endopeptidase TGAAGAAAAGGCCTTAGCAATTAAA

6-phosphofructo-2-

ASSAY0003 kinase/fructose-2,6-

Hs00190079 ml PFKFB3 biphosphatase 3 TGCCCAGATCCTGTGGGCCAAAGCT

ASSAY0006 solute carrier family 12

(potassium/chloride

Hs00220373 ml SLC12A9 transporters), member 9 CTCCGGCCTCGGTGGCATGAAGCCC cysteine-rich secretory

ASSAY0010 protein LCCL domain

Hs00230322 ml CRISPLD2 containing 2 CAGTCTGAAAGCCTGGGGACTCCTC glyceraldehyde-3-

ASSAY001 1 phosphate

Hs99999905 ml GAPDH dehydrogenase GGGCGCCTGGTCACCAGGGCTGCTT ubiquitin-conjugating

ASSAY0013 enzyme E2B (RAD6

Hs00163311 ml UBE2B homolog) CACCTTTTGAAGATGGTACTTTTAA mitogen-activated protein

ASSAY0017 kinase kinase kinase

Hs00179345 ml MAP4K1 kinase 1 CTCTCTCAGGAAAGACCCCCCACCT

ASSAY0027 Hs00191312 ml NMT2 N-myristoyltransferase 2 TTCGGATTTATGACAGTGTGAAGAA

Yip1 domain family,

ASSAY0040

Hs00219196 ml YIPF1 member 1 TGGGCTGCTTGGCATACTTTTTTGA

ASSAY0044 Hs00219931 ml LARS leucyl-tRNA synthetase I I I I CAGCAGATGGAATGCGTTTGG chromosome 3 open

ASSAY0045

Hs00220172 ml C3orf37 reading frame 37 TTTGAGAAGGATGCAGACTCATCTG

ASSAY0046 enhancer of yellow 2

Hs00220176 ml ENY2 homolog (Drosophila) CGCGGTGATGGTGGTTAGCAAGATG peter pan homolog

ASSAY0047 PPAN; (Drosophila);PPAN-

Hs00220301 ml PPAN-P2RY1 1 P2RY1 1 readthrough ATCAACGTGCACAAGGTGAACCTGA chromosome 1 open

ASSAY0048

Hs00220428 ml C1 orf63 reading frame 63 ATGGTGCAAAGCCTGAACTGTCGGA myotubularin related

ASSAY0056

Hs00221562 ml MTMR3 protein 3 TGTGCAGACCAGGGGAGCATGTAAC

SAM domain, SH3

ASSAY0060 domain and nuclear

Hs00223275 ml SAMSN1 localization signals 1 GATGATTCAACTGAGGCACATGAAG

PAP associated domain

ASSAY0062

Hs00223727 ml PAPD5 containing 5 TTTACAACCAGGTAACGATGTTGGA

ASSAY0063 Hs00223860 ml ZMAT3 zinc finger, matrin type 3 AGTACAGAATAATTCAGCAGGTCCT ASSAY0065 CREB regulated

Hs00224328 ml CRTC3 transcription coactivator 3 TACCTCCCAGATGGTGTCCTCAGAC jumonji domain containing

ASSAY0067

Hs00224851 ml JMJD4 4 GTGCACAACCTGGATGACACCATCT tumor necrosis factor,

ASSAY0074 alpha-induced protein 8-

Hs00226190 ml TNFAIP8L2 like 2 CCCAGCACAGCAGTGACTGACCACA

ADP-dependent

ASSAY0084

Hs00229849 ml ADPGK glucokinase GCATTGTCCATCAGGTCTTTCCCGC

ASSAY0085 anterior pharynx defective

Hs00229911 ml APH1 B 1 homolog B (C. elegans) TCATCGCCGGAGCTTTCTTCTGGTT sodium channel modifier

ASSAY0086

Hs00276716 ml SCNM1 1 TGCCGCCGGAAGTACAGACCAGAAG

SWI/SNF related, matrix

associated, actin

ASSAY0089 dependent regulator of

chromatin, subfamily a,

Hs00231324 ml SMARCA4 member 4 GAATCCTCACCAGGACCTGCAAGCG

ASSAY0092 transcription factor-like 5

Hs00232444 ml TCFL5 (basic helix-loop-helix) AAAGAGATAGAAGGCGCAGAATCCG membrane metallo-

ASSAYQ098

Hs00153519 ml MME endopeptidase TCCAGGCAATTTCAGGATTATTGGG caspase 6, apoptosis-

ASSAY0103 related cysteine

Hs00154250 ml CASP6 peptidase GTGTTACTCTGTTGCAGAAGGATAT acyloxyacyl hydrolase

ASSAY0107

Hs00155735 ml AOAH (neutrophil) CAAGAAATGGTGCATCTTCCCGAAA epoxide hydrolase 2,

ASSAY01 12

Hs00157403 ml EPHX2 cytoplasmic ACGTGACAGTAAAGCCCAGGGTCCG major histocompatibility

ASSAY01 14 complex, class II, DO

Hs00157950 ml HLA-DOB beta ACAGACTCTCCAGAAGA I I I I GTGA interferon regulatory

ASSAY01 17

Hs001581 14 ml IRF5 factor 5 ACACCATCTTCAAGGCCTGGGCCAA

ASSAY01 19 Hs00159537 ml NBN nibrin CCCGGCAGGAGGAGAACCATACAGA

ASSAY0120 nardilysin (N-arginine

Hs00159668 ml NRD1 dibasic convertase) TGTCACAAGCACAGAATCTATGGAT protein phosphatase 1 ,

ASSAY0124 catalytic subunit, beta

Hs00160349 ml PPP1 CB isozyme CGAGCTCATCAGGTGGTGGAAGATG

ASSAY0126 Hs00162077 ml SOAT1 sterol O-acyltransferase 1 CCATCTTGCCAGGTGTGCTGATTCT

Bruton

ASSAY0128 agammaglobulinemia

Hs00163761 ml BTK tyrosine kinase GTCAGGACTGAGCACACAGGTGAAC coagulation factor V

ASSAY0129 (proaccelerin, labile

Hs00164521 ml F5 factor) CGAGGAATACAGAGGGCAGCAGACA

ASSAY0136 DnaJ (Hsp40) homolog,

Hs00170600 ml DNAJA3 subfamily A, member 3 TCAACGTGACGATCCCCCCTGGGAC

ASSAY0141 Hs00173570 ml GRN granulin GTCGGACGCAGGCAGACCATGTGGA

ASSAY0142 Hs00174097 ml IL1 B interleukin 1 , beta GGATATGGAGCAACAAGTGGTGTTC angiotensin I converting

ASSAY0147 enzyme (peptidyl-

Hs00174179 ml ACE dipeptidase A) 1 AAGGACTTCCGGATCAAGCAGTGCA

ASSAY0149 Hs00174659 ml SIGLEC5 sialic acid binding Ig-like GTACCATCACCTCGGGTTCCAGGAA lectin 5

ASSAY0150 Hs00174705 ml CD163 CD163 molecule ACCTGCTCAGCCCACAGGGAACCCA

ASSAY0151 bactericidal/permeability-

Hs00175186 ml BPI increasing protein AAGCTGGATAGGCTGCTCCTGGAAC

ASSAY0152 Hs00175188 ml CTSC cathepsin C CGGTTATGGGACCACAAGAAAAAAA

ASSAY0154 Hs00175407 ml CTSS cathepsin S TGTGAAAAACAGCTGGGGCCACAAC peptidoglycan recognition

ASSAY0155

Hs00175475 ml PGLYRP1 protein 1 GCGACGTGGGCTACAACTTCCTGAT

ASSAY0156 Hs00175573 ml AQP9 aquaporin 9 CATCTTGATTGTCCTTGGATGTGGC inositol 1 ,4,5-

ASSAY0158

Hs00176666 ml ITPKB trisphosphate 3-kinase B GCAAGATGGGAATCAGGACCTACCT

ASSAY0160 Hs00176973 ml PRKCA protein kinase C, alpha GAACCACAAGCAGTATTCTATGCGG

ADAM metallopeptidase

ASSAY0164 domain 9 (meltrin

Hs00177638 ml ADAM9 gamma) TGCCACTGGGAATGCTTTGTGTGGA serine/threonine kinase

ASSAY0165

Hs00177790 ml STK17B 17b TGATATTGGAATATGCTGCAGGTGG

ASSAY0168 Hs00179987 ml FHIT fragile histidine triad gene CACC I I I I CCATGCAGGATGGCCCC insulin-like growth factor 2

ASSAY0171

Hs00181419 ml IGF2R receptor CTTCTGCAGACACTCAAACAGCTAC

ASSAY0174 Hs00183425 ml SMAD2 SMAD family member 2 TGGACACAGGCTCTCCAGCAGAACT

ATPase, H+ transporting,

ASSAY0176 lysosomal 42kDa, V1

Hs00184625 ml ATP6V1 C1 subunit C1 ACCTTCCTG G AATCTCTCTTG ATTT nuclear receptor

ASSAY0178

Hs00186661 ml NCOA1 coactivator 1 CACCTCAGCCACCCCTGAATGCTCA

ASSAY0180 Hs00187845 ml BCL2A1 BCL2-related protein A1 AAAACGGAGGCTGGGAAAATGGCTT

BCL2-associated

ASSAY0183

Hs00188713 ml BAG 3 athanogene 3 GGGCCCCAAGGAGACTCCATCCTCT cytochrome b-245, alpha

ASSAY0194

Hs00164370 ml CYBA polypeptide GGCCTGATCCTCATCACCGGGGGCA

S100 calcium binding

ASSAY0197

Hs00170953 ml S100A6 protein A6 CCCTACCGCTCCAAGCCCAGCCCTC tumor necrosis factor

ASSAY0198 (TNF superfamily,

Hs00174128 ml TNF member 2) TAGCCCATGTTGTAGCAAACCCTCA

ASSAY0199 Hs00175295 ml TCF12 transcription factor 12 GCGCTTGATCCCTTGCAAGCAAAAA transforming, acidic

ASSAY0200 coiled-coil containing

Hs00180691 ml TACC1 protein 1 GTCCACTGTGCTTGGGCTGCTGGAG src kinase associated

ASSAY0202

Hs00182698 ml SKAP2 phosphoprotein 2 CCTCTGATGGAGCCCAGTTTCCTCC

ASSAY0204 Treacher Collins-

Hs00184390 ml TCOF1 Franceschetti syndrome 1 GCATCTCCAGCACAGGTGAAAACCT

ASSAY0209 Hs00200082 ml UBL3 ubiquitin-like 3 CAATTGGCCAATGGACTGGGAAGAA coiled-coil domain

ASSAY0210

Hs00203291 ml CCDC106 containing 106 CTCGGATGGAGGCAGAGGACCACTG

RNA binding motif protein

ASSAY0215

Hs00208212 ml RBM19 19 ACGAGCCACTAAGCCAGCCGTGACA transmembrane protein

ASSAY0221

Hs00215267 ml TMEM127 127 CCCGGACCTGCTGAAAGATTTCTGC

ASSAY0222 membrane-associated

Hs00215631 ml MARCH 1 ring finger (C3HC4) 1 AGGACATCTGCAGAATCTGTCACTG ASSAY0226 Hs00220138 ml LXN latexin ACAAGCCAGCATGGAGGATATTCCA tankyrase, TRF1 -

ASSAY0230 interacting ankyrin-related

Hs00228829 ml TNKS2 ADP-ribose polymerase 2 TGAAACAGCATTGCATTGTGCTGCT dynein heavy chain

ASSAY0246

Hs00330168 ml DNHD1 domain 1 GGGCGCTGGAGTCAAGTGACTCTAA ribosomal protein

SA;ribosomal protein SA

RPSA; pseudogene 19;ribosomal

ASSAY0247

RPSAP19; protein SA pseudogene

RPSAP58; 58;ribosomal protein SA

Hs00347791 s1 RPSAP9 pseudogene 9 GGTCTGCAGCTCCCACTGCTCAGGC golgin A8 family, member

ASSAY0251 GOLGA8B; B;golgin A8 family,

Hs00367259 ml GOLGA8A member A AGAAGCCGGATGGGTTCTCGAGCCG

ASSAY0257 DnaJ (Hsp40) homolog,

Hs00397335 ml DNAJC13 subfamily C, member 13 GGTCCAAAGGTTCGAATTACGTTAA

LysM, putative

ASSAY0258 peptidoglycan-binding,

Hs00406040 ml LYSMD3 domain containing 3 TTGTACGGTAGCAGATATCAAGAGA

SH3 domain binding

ASSAY0265 glutamic acid-rich protein

Hs00606772 g1 SH3BGRL3 like 3 CACCGGCTCCCGCGAAATCAAGTCC

ASSAY0267 Hs00609831 g1 AARS alanyl-tRNA synthetase CGGCGCCTCAGCCAAGGCCCTGAAT

RNA binding motif protein

ASSAY0268

Hs00705337 s1 RBM39 39 AAC AG C AG C ATATG TAC CTCTTCC A

SUB1 homolog (S.

ASSAY0269

Hs00743451 s1 SUB1 cerevisiae) AACTTAATCTCTTCATGTTCAGTTT protein tyrosine

ASSAY0270 phosphatase type IVA,

Hs00754750 s1 PTP4A2 member 2 CCTTTTCCCCCGATCCAAGTTGTAG

ASSAY0278 Hs01092416 s1 N/A N/A GTGTGAAGATCCAGCCTGATGCCCA

ASSAY0280 Hs01681736 s1 EP400NL EP400 N-terminal like GATATGAATGAATGCTGTGTGGAGC

ATP-binding cassette,

ASSAY0284 sub-family A (ABC1 ),

Hs00194045 ml ABCA1 member 1 ACCCAATCCCAGACACGCCCTGCCA actin related protein 2/3

ASSAY0289 complex, subunit 1 B,

Hs00194815 ml ARPC1 B 41 kDa CGCGGGAGGAGCCAAGCCGCCATGG

ASSAY0290 survival motor neuron

Hs00195343 ml SMNDC1 domain containing 1 GTGAAGATGGACAGTGTTATGAAGC

Taxi (human T-cell

ASSAY0292 leukemia virus type I)

Hs00195718 ml TAX1 BP1 binding protein 1 AAACAACTCTTGCAGGATGAGAAAG

ASSAY0293 choline/ethanolamine

Hs00196061 ml CEPT1 phosphotransferase 1 ACAGAGCAGGCACCTCTGTGGGCAT transcription elongation

ASSAY0302

Hs00198676 ml TCERG1 regulator 1 TACTCCATGGTGTGTCGTTTGGACT cyclin D-type binding-

ASSAY0315

Hs00201734 ml CCNDBP1 protein 1 TGCCGTCTCCACAGGAAACCCAGAA

ASSAY0319 Hs00202185 ml FTSJ1 FtsJ homolog 1 (E. coli) CTTAACCCATTACGCTGGCAAACTG nuclear prelamin A

ASSAY0320

Hs00202526 ml NARF recognition factor AAAAGTCTTGGGGTGCACTATGTAT

PRP6 pre-mRNA

ASSAY0321 processing factor 6

Hs00202956 ml PRPF6 homolog (S. cerevisiae) CGTGGCCAAGCTG I I I I GGAGTCAG phosphoinositide-3-

ASSAY0331 kinase, regulatory subunit

Hs00204803 ml PIK3R5 5 AGAAGACCCGAGAGGTCCAGGAGAA

SEC24 family, member D

ASSAY0335

Hs00207926 ml SEC24D (S. cerevisiae) CAGCAAGCCAGCTTATTCTACCAGA

IQ motif and Sec7 domain

ASSAY0336

Hs00208333 ml IQSEC1 1 ACCTCCGAGGTGTGGACGATGGTGA

NEDD4 binding protein 2-

ASSAY0337

Hs00208459 ml N4BP2L2 like 2 ATTGTCTCGAATTCTGCTTGGTCAG signal-induced

ASSAY0340 proliferation-associated 1

Hs00210194 ml SIPA1 L1 like 1 ACTAGAGAGGCGGCTGTCTCCTGGT

SH3 domain containing,

ASSAY0341 Ysc84-like 1 (S.

Hs00210368 ml SH3YL1 cerevisiae) ATCATGAGAGAGTTGGCAATTTGAA

ASSAY0342 Hs00210626 ml VI LL villin-like GGAAGGTGGAGGTGTGGTGCATCCA

ASSAY0344 family with sequence

Hs0021 1234 ml FAM164A similarity 164, member A ACATAGCCAGGCCAGATGGGGACTG transmembrane emp24

ASSAY0345 protein transport domain

Hs0021 1349 ml TMED5 containing 5 ATCAGATGGAGTTCACACTGTAGAG calcium binding protein

ASSAY0348

Hs00212451 ml CAB39 39 GCTCATTGACTTTGAGGGCAAAAAA zinc finger, C3HC-type

ASSAY0351

Hs00212862 ml ZC3HC1 containing 1 CCATCCCCAGACCGATTTGGGATGT zinc finger, DHHC-type

ASSAY0354

Hs00213209 ml ZDHHC3 containing 3 TCGTCCTGTTTACAATGTACATAGC

Smg-6 homolog,

nonsense mediated

ASSAY0355

mRNA decay factor (C.

Hs00214019 ml SMG6 elegans) CCCCTCATCGTGATCAATGAGCTGG

ASSAY0356 family with sequence

Hs00214159 ml FAM46A similarity 46, member A ACTCACGCTCAAGGAAGCTTATGTG

ASSAY0357 Hs00214281 ml AFTPH aftiphilin TATGCAGCAGGATTGGGTATGTTAG

ASSAY0362 membrane-associated

Hs00215155 ml MARCH5 ring finger (C3HC4) 5 CCAAAATTGGGTCCAGTGGTTTACG arginine and glutamate

ASSAY0367

Hs00215976 ml ARGLU1 rich 1 AGCCAAACTGGCCGAAGAACAGTTG

TBC1 domain family,

ASSAY0374

Hs00218284 ml TBC1 D2 member 2 CTTCTGACGAAGTGCGCCTACCTCC activin A receptor, type

ASSAY0380

Hs00609603 ml ACVR2B MB ATTGCCCACAGG G ACTTTA AAAGTA

MYST histone

ASSAY0391

Hs00272972 ml MYST2 acetyltransferase 2 CCAGGCACCAGGCACCAACGGAGAG acyl-CoA synthetase

ASSAY0392 short-chain family

Hs00287264 ml ACSS1 member 1 TGGGGTCAGTGGGAGAGCCCATCAA

ASSAY0393 Hs00295454 s1 N/A N/A AGCTAAGAGGTTTCCAGTGCAATAC tet oncogene family

ASSAY0394

Hs00325999 ml TET2 member 2 GGCAGCACATTGGTATGCACTCTCA

RAD54-like 2 (S.

ASSAY0400

Hs00379387 ml RAD54L2 cerevisiae) GGCTGCCTCAGGTTCCCAGGGACCT

TRAF2 and NCK

ASSAY04Q2

Hs00390635 ml TNIK interacting kinase ACCCATCAGAGCAAGCAACCCTGAT

T cell receptor alpha

ASSAY0405

Hs00415453 g1 TRA@ locus TGGATTCAGTTGGCATGGGTGAGCA

ASSAY0407 Hs00540709 s1 TMEM203 transmembrane protein CGGGAGCTGGTGCAGTGGCTAGGCT 203

complement component

ASSAY0408 (3b/4b) receptor 1 (Knops

Hs00559348 ml CR1 blood group) TGTTCCTGCTGCCTGCCCACATCCA

ATPase, H+ transporting,

ASSAY0409 lysosomal 13kDa, V1

Hs00606257 ml ATP6V1 G1 subunit G1 CCCGCAAAAGAAAGAACCGGAGGCT

ASSAY0420 Hs00609515 ml CD247 CD247 molecule GCCTTTACCAGGGTCTCAGTACAGC

ASSAY0421 Hs00609836 ml AARS alanyl-tRNA synthetase CAAAATTTGGGGCTGGATGACACCA

PWP2 periodic

ASSAY0425 tryptophan protein

Hs00610478 ml PWP2 homolog (yeast) GGCTGGCCAAGTACTTCTTCAATAA neural precursor cell

expressed,

ASSAY0427

developmental^ down-

Hs00610590 ml NEDD9 regulated 9 GGAACATCATCAGCTGAGCCAGTTC

T cell receptor alpha

ASSAY0431

Hs00612292 ml TRA@ locus CTGTGTTTCTG ACCTTTG GAACTAT

YTH domain family,

ASSAY0433

Hs00697331 ml YTHDF1 member 1 TGGTGCGCAAGGAACGGCAGAGTCG

ASSAY0435 Hs00702769 s1 MARCKSL1 MARCKS-like 1 GTCCCCCCCAAGGAGACCCCCAAGA nuclear factor, interleukin

ASSAY0437

Hs00705412 s1 NFIL3 3 regulated ACTCTCCACAAAGCTCGCTGTCCGA

ASSAY0440 Hs00706419 s1 SELT selenoprotein T ACATGATTGAGAACCAGTGTATGTC

ASSAY0441 presenilin enhancer 2

Hs00708570 s1 PSENEN homolog (C. elegans) TGGGGCCCTGCTTATTCTCCCAGGA

U2 small nuclear RNA

ASSAY0442

Hs00733884 ml U2AF1 auxiliary factor 1 CTGACGGCTCACACTACCATTGCCC

L antigen family, member

ASSAY0449

Hs00741 181 g1 LAGE3 3 AGGATCCTGGTCGTCCGCTGGAAAG chromosome 18 open

ASSAY0450

Hs00743508 s1 C18orf32 reading frame 32 AGGTAGAA I I I I G G G AG G T AATAAT

ADP-ribosylation factor¬

ASSAY0456

Hs00750443 s1 ARL8B like 8B GTGTGACTCTGTGGGGACTGCATAG mitochondrial

ASSAY0460 translational release

Hs00759012 s1 MTRF1 L factor 1 -like CGGACTAAGGATGCGGTCCCGGGTT

ASSAY0463 Hs00762481 s1 RPL36 ribosomal protein L36 CCTTCTCCCCGTCGCTGTCCGCAGC

ASSAY0472 natural killer-tumor

Hs00234637 ml NKTR recognition sequence AATCGGCGGTCCAGGAGTTGTAGAT

ASSAY0480 hematopoietically

Hs00242160 ml HHEX expressed homeobox ACCCCCTGGGCAAACCTCTACTCTG

ASSAY0484 cell division cycle 25

Hs00244740 ml CDC25B homolog B (S. pombe) GGCGGAGCAGACGTTTGAACAGGCC

ASSAY0489 Hs00248408 ml Sep-06 septin 6 AGAAAGAGCTGCACGAGAAGTTTGA

ASSAY0501 Hs00256990 ml CENPO centromere protein O CGGCGAGCCAGCGTGAAAGCATGTA chromosome 5 open

ASSAY0513

Hs00260900 ml C5orf32 reading frame 32 CAGGAGCCTCCTAAAACCACAGTGT

ASSAY0514 piggyBac transposable

Hs00261275 ml PGBD1 element derived 1 AGTCAGGTCCCAGACATTGGTGAAG pyridine nucleotide-

ASSAY0517 disulphide oxidoreductase

Hs00261978 ml PYROXD2 domain 2 TGGTGGCTGCAGCGTACCTGCAGAG ASSAY0526 DnaJ (Hsp40) homolog,

Hs00266011 ml DNAJA1 subfamily A, member 1 CTCAGCCCGCACCGGCAGTAGAAGA eukaryotic translation

ASSAY0527 initiation factor 3, subunit

Hs00266036 ml EIF3E E TTATCAGCCACAATATCTTAATGCA sortilin-related receptor,

ASSAY0535 L(DLR class) A repeats-

Hs00268342 ml SORL1 containing CAACAAGCGGTACATCTTTGCAGAC

G protein-coupled

ASSAY0537

Hs00269247 s1 GPR65 receptor 65 TTCTCTCCTGCCTTGTGCAAAGGGA beta-site APP-cleaving

ASSAY0548

Hs00273238 ml BACE2 enzyme 2 ACACTTGCCAAGCCATCAAGTTCTC

N-acetyltransferase 6

ASSAY0549

Hs00273329 s1 NAT6 (GCN5-related) CCGCACCTCCCGCCTGCACTCCCTG

ASSAY0550 leucine zipper, down-

Hs00273392 s1 LDOC1 regulated in cancer 1 AACCCCAGCTATTGGCCAGGCCCCT glycogen synthase kinase

ASSAY0553

Hs00275656 ml GSK3B 3 beta AGAAATAATCAAGGTCCTGGGAACT

ASSAY0555 Hs00276784 ml N/A N/A N/A

H3 histone, family 3B

ASSAY0558

Hs00287906 s1 H3F3B (H3.3B) GCTGTATTTGCAGTGTGGGCTAAGA

ASSAY0559 Hs00291515 ml IKBIP IKBKB interacting protein TAATTTCAGAAAAGCTTGAGTCTAC

COMM domain containing

ASSAY0562

Hs00292593 ml COMMD7 7 GGGCGCGCAGCAGTTCTCAGCCCTG coiled-coil domain

ASSAY0569

Hs00299171 ml CCDC127 containing 127 TTGGCTGC I I I I CGTTGGATTTGGT

ASSAY0572 proline, glutamate and

Hs00300396 ml PELP1 leucine rich protein 1 TCTCTCAAAGGCAAGCTGGCCTCAT

ASSAY0577 HECT, UBA and WWE

Hs00328354 ml HUWE1 domain containing 1 GAAAAAGATCAGATGGGGAACAGGA chemokine (C-C motif)

ASSAY0584

Hs00356601 ml CCR2 receptor 2 GCCACAAGCTGAACAGAGAAAGTGG cysteine-rich with EGF-

ASSAY0588

Hs00360923 g1 CRELD2 like domains 2 TCCAAGTACGAGTCCAGCGAGATTC cannabinoid receptor 2

ASSAY0591

Hs00361490 ml CNR2 (macrophage) ACAACACAACCCAAAGCCTTCTAGA leucine-rich alpha-2-

ASSAY0597

Hs00364835 ml LRG1 glycoprotein 1 ACCAAAAAGCCCAGGGGGCATTCAA non-protein coding RNA

ASSAY0598

Hs00364877 ml NCRNA00219 219 AAAGGTGACCTGAAGGATGTCCTTG

RAB24, member RAS

ASSAY0599

Hs00365678 g1 RAB24 oncogene family GTATTTGGGACACAGCAGGCTCTGA

ASSAY0608 family with sequence

Hs00370691 ml FAM1 13B similarity 1 13, member B TACTTTAATGACCATCCGCAGAGCC

GRB2-associated binding

ASSAY0614

Hs00373045 ml GAB2 protein 2 GAGAGCACAGACTCCCTGAGAAATG amyloid beta (A4)

precursor protein-binding,

ASSAY0624

family B, member 1

Hs00377427 ml APBB1 (Fe65) TCCCCAG AG G ACACAG ATTCCTTCT complement component

ASSAY0637

Hs00383718 ml C5AR1 5a receptor 1 AGACCAGAACATGAACTCCTTCAAT biorientation of

ASSAY0643 chromosomes in cell

Hs00386037 ml BOD1 L division 1 -like CAGAGGCTCAGAGATCAAAGACACA ASSAY0645 mitogen-activated protein

Hs00387426 ml MAP2K4 kinase kinase 4 CAAATAATGGCAGTTAAAAGAATTC

Smg-6 homolog,

nonsense mediated

ASSAY0651

mRNA decay factor (C.

Hs00391737 ml SMG6 elegans) ACGCAAGACAGTAAAATATGCCTTG

ASSAY0653 Hs00393297 ml ZNF512B zinc finger protein 512B TGGTAAGAAAAGGGCTGCGGACAGC leukocyte specific

ASSAY0655

Hs00394683 ml LST1 transcript 1 AGGCCACAAGCTCTGGATGAGGAAC

ASSAY0656 Hs00395045 ml STMN3 stathmin-like 3 CCAGTACGGGGACATGGAGGTGAAG jumonji domain containing

ASSAY0661

Hs00405469 ml JMJD1 C 1 C TCAAAAGCAGGAATTCTCAAGAAAT

ASSAY0664 Hs00405872 ml CYTSA cytospin A GTGCAGCGCGTGTTCTTGGGGAAGA leucine-rich repeat kinase

ASSAY0668

Hs0041 1 197 ml LRRK2 2 GACAAGAACAAGCCAACTG I I I I CT

PHD and ring finger

ASSAY0670

Hs0041 1807 ml PHRF1 domains 1 GTGCAGAAGATCTGCCACAGCAAGA

ASSAY0671 Hs00412084 ml RFTN1 raftlin, lipid raft linker 1 CCGACAGATCTCAGAAAACTGATCT

ASSAY0674 glioma tumor suppressor

Hs00414236 ml GLTSCR2 candidate region gene 2 CGCACGAGCGGTGGCTTGTTGTCAG ankyrin repeat domain

ASSAY0677

Hs00414889 ml ANKRD36B 36B GAAGGAAAGGACTGCCCTACATTTG inscuteable homolog

ASSAY0682

Hs00416940 ml INSC (Drosophila) TGGCCTGCCTGGCTGCTCTGCGTAG small nucleolar RNA host

ASSAY0683 gene 6 (non-protein

Hs00417251 ml SNHG6 coding) TAGCTGGGCTCTGCGAGGTGCAAGA leucine-rich repeat kinase

ASSAY0684

Hs00417273 ml LRRK2 2 TTTGGCCCTCCTCACTGAGACTATT

ASSAY0691 family with sequence

Hs00420179 ml FAM159A similarity 159, member A ACAGACAGCAGGCCCTGAGGAGGTT lysozyme (renal

ASSAY0692

Hs00426231 ml LYZ amyloidosis) TATCCTGCAGTGCTTTGCTGCAAGA protein phosphatase 2,

ASSAY0693 catalytic subunit, alpha

Hs00427259 ml PPP2CA isozyme GAAGTTCCCCATGAGGGTCCAATGT tumor necrosis factor

receptor superfamily,

ASSAY0695 member 10c, decoy

without an intracellular

Hs00427795 g1 TNFRSF10C domain CGGAAGTGTAGCAGGTGCCCTAGTG

ASSAY0699 Hs00429452 ml VPREB3 pre-B lymphocyte 3 CCTTCCTGTCAGTTTCCCAGACAGT shisa homolog 5

ASSAY0702

Hs00429977 ml SHISA5 (Xenopus laevis) CCGGGTGCACGTGGTGAGGTGTGTA signal-regulatory protein

ASSAY0706

Hs00431040 g1 SIRPG gamma CAGAAGACCTGACTCTCCTTCCTTC

ASSAY0709 mitochondrial GTPase 1

Hs00536594 ml MTG1 homolog (S. cerevisiae) CAGCGCTTTGGGTACGTGCAGCACT chromosome 5 open

ASSAY0713

Hs00538077 ml C5orf41 reading frame 41 ACACCCACAGACAGCATCGCACAGA coiled-coil domain

ASSAY0720

Hs00540812 ml CCDC101 containing 101 AGAGGCTGAGTG C AAC ATC CTTCG G

ASSAY0734 hematological and

Hs00602957 ml HN1 neurological expressed 1 CCAAGTCAGCAGGTGCCAAGTCTAG tumor necrosis factor

ASSAY0741 receptor superfamily,

Hs00606874 g1 TNFRSF13C member 13C CGGAGACAAGGACGCCCCAGAGCCC

Sfi1 homolog, spindle

ASSAY0745 assembly associated

Hs00826823 ml SFI 1 (yeast) GCAGAACCTCTGGTCCTGTCGGCGG

ASSAY0750 Hs00846452 s1 RNF208 ring finger protein 208 CCACGTGCGGAACCCACTGTCCGCC protein-kinase, interferon- inducible double stranded

ASSAY0751 RNA dependent inhibitor,

repressor of (P58

Hs00852410 g1 PRKRIR repressor) TACTCTGCAGTGCAGTGTCAGATTT

ASSAY0752 Hs00854645 g1 BRI3 brain protein I3 CCTTCCTGGGCATCTTCCTGGCCAT deleted in lymphocytic

ASSAY0754 leukemia 2 (non-protein

Hs00867656 s1 DLEU2 coding) AAAAATTTA I I I I ACACATGTCAAG

ASSAYQ75S Hs00891617 s1 N/A N/A ACAGTTGTTTATGGTAGGAGGACTA ribosomal protein L32

ASSAY0758

Hs00898410 g1 RPL32P3 pseudogene 3 GCTGGCAGGCACCATGTCGTCCTGT interleukin 23, alpha

ASSAY0759

Hs00900829 g1 IL23A subunit p19 CCTCAGCCAACTCCTGCAGCCTGAG mediator complex subunit

ASSAY0762

Hs00902624 ml MED6 6 AGAAAAGCCTGTTCCAGTGGATCAA

ASSAY0763 transformer 2 beta

Hs00907493 ml TRA2B homolog (Drosophila) ATCAGATTTATAGAAGGCGGTCACC

ASSAY0766 Hs00918972 ml TCF12 transcription factor 12 AACATCAGCCAGTTCCAGAGTTATC

RNA binding motif protein

ASSAY0767

Hs00921653 ml RBM19 19 CCGCTCACTTTCACGAGCCCCCGAA

ASSAY0773 Hs00932180 g1 RPS5 ribosomal protein S5 TGACATTTCCCTGCAGGATTACATT synaptojanin 2 binding

ASSAY0774

Hs00935093 ml SYNJ2BP protein AG C AC AG GTT AC AG G TG C AG AATG G

ASSAY0778 Hs00939205 ml RNF24 ring finger protein 24 GCCTTCCACAGAAAGTGCCTTATTA

ASSAY0782 Hs00945401 ml ANXA1 annexin A1 TGCCAAGCCATCCTGGATGAAACCA

ST6 beta-galactosamide

ASSAY0784 alpha-2,6-sialyltranferase

Hs00949382 ml ST6GAL1 1 CCAAAGTGGTACCAGAATCCGGATT

ASSAY0790 chaperonin containing

Hs00963390 g1 CCT8 TCP1 , subunit 8 (theta) GTGGTTTTTAAGCATGAAAAGGAAG

ASSAY0792 DnaJ (Hsp40) homolog,

Hs00967069 ml DNAJC13 subfamily C, member 13 AGCAGGATACCTCACAGGACCTGGA

ASSAY0793 Hs00967250 ml BRP44 brain protein 44 AGCTTTTTCGTATTTGGAGATATAA

SUB1 homolog (S.

ASSAY0794

Hs00970533 g1 SUB1 cerevisiae) GTTGACAAAAAGTTAAAGAGGAAAA

ASSAY0795 Hs00971411 ml ANXA3 annexin A3 TTACTGTTGGCCATAGTTAATTGTG ciliary rootlet coiled-coil,

ASSAY0801

Hs00985988 g1 CROCC rootletin CCGCCAGAGGGTGTCCACACTGAAG

ASSAY0806 Hs00997789 ml PSEN1 presenilin 1 TTC ATTTACTTG GGGGAAGTGTTTA

ASSAY0809 cytokine inducible SH2-

Hs01003603 ml CISH containing protein TGCGTTCAGGGACCTCGTCCTTTGC

ASSAY081 1 dihydroxyacetone kinase

Hs01008103 ml DAK 2 homolog (S. cerevisiae) AGCCGTGCGGCCAGAGCAATCCAGG actin related protein 2/3

ASSAY0820 complex, subunit 2,

Hs01031740 ml ARPC2 34kDa TGAAAACAATCACGGGGAAGACGTT

ST6 (alpha-N-acetyl- neuraminyl-2,3-beta- galactosyl-1 ,3)-N-

ASSAY0821

acetylgalactosaminide

alpha-2,6-

Hs01032565 ml ST6GALNAC2 sialyltransferase 2 CCTGTGACCAGGTCAGTGCCTATGG

ASSAY0822 Hs01032700 ml LBR lamin B receptor TTATTGTTCTGAAACTTTGTGGTTA

ASSAY0826 Hs01036536 ml BCR breakpoint cluster region ATTGCTGTGGTCACCAAGAGAGAGA

ASSAY0833 Hs01051024 g1 SETDB1 SET domain, bifurcated 1 TCCCAACCCTTCTTGAACTGGGTCT

ASSAY0835 Hs01053640 ml TXK TXK tyrosine kinase GCTGGCATGAGAAACCTGAAGGCCG

ASSAY0838 DEAD (Asp-Glu-Ala-Asp)

Hs01056146 ml DDX21 box polypeptide 21 AAC AG AAAT AC AG G AG AAATG G CAT

ASSAY0842 thioredoxin-related

Hs01062739 ml TMX4 transmembrane protein 4 TCTGAGCGTTCTGAGCAGAATCGGA

ASSAY0843 Hs01064052 g1 SEPX1 selenoprotein X, 1 TTGTCCCTAAAGGCAAAGAAACTTC

ASSAY0850 Hs01075667 ml IL6R interleukin 6 receptor GCACGCCTTGGACAGAATCCAGGAG

ASSAY0859 Hs01090047 ml PRKCD protein kinase C, delta AGGACATCCTGGAGAAGCTCTTTGA v-ral simian leukemia viral

ASSAY0862 oncogene homolog B (ras

related; GTP binding

Hs01095303 ml RALB protein) AACGTGGACAAGGTGTTCTTTGACC

ASSAY0863 Hs01 102345 ml RPL37A ribosomal protein L37a GCGGTGCCTGGACGTACAATACCAC

ASSAY0867 Hs01 1 10945 ml ADA adenosine deaminase GTTT AAAAG G CTG AAC ATC AATG C G zinc finger, DHHC-type

ASSAY0876

Hs01372307 ml ZDHHC18 containing 18 ACCTCCCAGCCTAATTGACCGGAGG hypothetical protein

ASSAY0879

Hs01395179 ml LOC100131564 LOC100131564 CTCAGATTTTGAGCAAACAAAGCTC

ASSAY0883 Hs01553131 ml FNBP4 formin binding protein 4 TGGTTAGTGGCATGGCAGAGAGAAA

GLI pathogenesis-related

ASSAY0886

Hs01564142 ml GLIPR1 1 CTATACATGACTTGGGACCCAGCAC deltex homolog 3

ASSAY0897

Hs01595350 ml DTX3 (Drosophila) CCGGTGTCCAGGGGGCTGAACACCC

ASSAY0904 Hs01885851 s1 LTB4R2 leukotriene B4 receptor 2 CTACGGCCTTGGCCTTCTTCAGTTC solute carrier family 25,

ASSAY0907

Hs01908739 s1 SLC25A45 member 45 CAAAGGAGGTGGTGTCTGTCAGTCA

ASSAY091 1 Hs01926559 g1 RPL13A ribosomal protein L13a CTGGGAAGATGCACAACCAAGGGGT

ASSAY0913 HsO 1945436 u1 RPS13 ribosomal protein S13 GTCCTCCCTCCCAATTGGAAATATG olfactory receptor, family

ASSAY0914 52, subfamily K, member

Hs023391 16 s1 OR52K1 1 GGCAGTTCTCCAGCTTGCCTCTCAG dihydropyrimidine

ASSAY0919

Hs02510591 s1 DPYD dehydrogenase GATGGGTGTACAAACTCATCCTCTT guanine nucleotide

ASSAY0922 binding protein (G

GNG10; protein), gamma

Hs02597217 g1 LOC653503 10;GNG10 pseudogene GAG AG G ATC AAG GTCTCTCAGGCAG v-myc myelocytomatosis

ASSAY0931 viral oncogene homolog

Hs99999003 ml MYC (avian) GGAGACACCGCCCACCACCAGCAGC

ASSAY0935 Hs00991010 ml IL1 R1 interleukin 1 receptor, TATTACAGTGTGGAAAATCCTGCAA type I

phosphatidylinositol

ASSAY0939 binding clathrin assembly

Hs00999731 g1 PI CALM protein AAATGGAACCACTAAGAATGATGTA translocase of outer

ASSAY0944 mitochondrial membrane

Hs01587378 mH TOMM40 40 homolog (yeast) CCCACAGAGGCGTTCCCTGTACTGG

ASSAY0947 Hs00254569 s1 HRH2 histamine receptor H2 GGTCACCCCAGTTCGGGTCGCCATC chromosome 1 1 open

ASSAY0948

Hs00203146 ml C1 1 orf2 reading frame 2 ATCTCAG CCACAG ACACCATCCG G A death inducer-obliterator

ASSAY09S0

Hs01 123468 ml DID01 1 ATGCGGTGCTCAGGCAGGTATTAAA

NLR family, pyrin domain

ASSAY0957

Hs00536435 ml NLRP12 containing 12 ACTACGGACTTTGTGGCTGAAGATC

ASSAY0959 Hs00185574 ml EZR ezrin AAAATGCCGAAACCAATCAATGTCC

ASSAY0962 dehydrogenase/reductase

Hs0021 1306 ml DHRS7 (SDR family) member 7 CTTTAAGAGTGGTGTGGATGCAGAC mitochondrial ribosomal

ASSAY0964

Hs00375656 ml MRPL38 protein L38 ATTTCGGGGAGAAGACAGATCCCAA

ASSAY0966 Hs00323799 ml RNF160 ring finger protein 160 TGAAAAGGCATGTCCTAGTTCAGAT

ASSAY0968 Hs00209150 ml EPN2 epsin 2 AAAACAGCCGAATCTGTGACCTCTC

ASSAY0969 HECT, UBA and WWE

Hs00948075 ml HUWE1 domain containing 1 TCAATTGGCCAAGGTATTTCCCAGC multiple EGF-like-

ASSAY0971

Hs00391048 ml MEGF9 domains 9 GTGCAACAGTTCTGGGAAATGCCAG calmodulin 2

ASSAY0978 (phosphorylase kinase,

Hs00830212 s1 CALM2 delta) GTTTAGCCACTTAAAATCTGCTTAT zinc finger protein

ASSAY0990 ZNF655; 655;NudC domain

Hs00225286 ml NUDCD3 containing 3 CCCCTCCCCTCGTGATGGTCATTGT eukaryotic translation

ASSAY0994 initiation factor 4E nuclear

Hs00219784 ml EIF4ENIF1 import factor 1 TCAGAAACAGGCAACAGCGAGTGAC

ASSAY1006 Hs00228595 ml GON4L gon-4-like (C. elegans) GATGTGGGGAATGAAGATGAAGCAG

ASSAY1022 Hs00183764 ml PRDM4 PR domain containing 4 TCCCTGCCCCAGGCCTCCCAGTGGC

ASSAY1023 inositol 1 ,4,5-triphosphate

Hs01573555 ml ITPR3 receptor, type 3 GCTTCATCTGTGGTCTGGAGAGGGA cold shock domain

ASSAY1024 containing E1 , RNA-

Hs00918650 ml CSDE1 binding TAAAAGTAGGAGATGATGTTGAATT myeloid differentiation

ASSAY1025 primary response gene

Hs00182082 ml MYD88 (88) CCCAGCATTGAGGAGGATTGCCAAA spectrin, beta, non-

ASSAY1026

Hs00162271 ml SPTBN1 erythrocytic 1 GCTCTGGGCACACAGGTGAGGCAGC chromosome 16 open

ASSAY1029

Hs00203675 ml C16orf5 reading frame 5 TGCCTCCGGGTTTCTACCCTCCTCC

ASSAY1036 DCP1 decapping enzyme

Hs00218198 ml DCP1A homolog A (S. cerevisiae) CCATCCCGGTTGCAGGCGCCCCACT

TAF6 RNA polymerase II,

ASSAY1039 TATA box binding protein

(TBP)-associated factor,

Hs00425763 ml TAF6 80kDa GAGCCTCCTGCTGAAACACTGTGCT regulation of nuclear pre-

ASSAY1045 mRNA domain containing

Hs00399261 ml RPRD2 2 GGCTCCGGAGATCTGCATATCCCCA chitinase domain

ASSAY^"! 046

Hs00388156 ml CHID1 containing 1 GTTGTCGGGGCCAGGTACATCCAGA

ASSAY1052 Hs00391528 ml ANKRD17 ankyrin repeat domain 17 ACTAGAAGCTGCAGGAATAGGAAAA

ASSAY10S3 Hs00984230 ml B2M beta-2-microglobulin AAGCAGCATCATGGAGGTTTGAAGA

ASSAY 1057 Hs00200632 ml SYNRG synergin, gamma CCCAAGAAACCAGGCCCTTCCTTGG sorbin and SH3 domain

ASSAY1059

Hs00195059 ml SORBS3 containing 3 ATGGCTGGTTTGTGGGTGTCTCCCG two pore segment

ASSAY1061

Hs00330542 ml TPCN1 channel 1 TACCTCCAGGAAGGCGAGAACAACG

ASSAY1063 pogo transposable

Hs00418559 ml POGZ element with ZNF domain CAACAATGCTGGCAATCCTTTGGTC interleukin 2 receptor,

ASSAY1074

Hs00386697 ml IL2RB beta GAACACCGGGCCATGGCTGAAGAAG

ASSAY1078 HECT, UBA and WWE

Hs00229975 ml HUWE1 domain containing 1 TGAGAATGACAGGAGCCATCCGCAA

SWI/SNF related, matrix

associated, actin

ASSAY1082 dependent regulator of

chromatin, subfamily c,

Hs02559508 s1 SMARCC1 member 1 GGGAGGGAGTTTGGCAAGAATGGAG

ASSAY"! 084 ubiquitin protein ligase E3

Hs00390223 ml UBR4 component n-recognin 4 ACATGACCACAGGTACAGAATCAGA glutamate-ammonia

ASSAY1088 ligase (glutamine

Hs00374213 ml GLUL synthetase) TTTCTGTGGCTGGGAACACCTTCCA serine threonine kinase

ASSAY1090 39 (STE20/SPS1

Hs00202989 ml STK39 homolog, yeast) GAGGTTATCGGCAGTGGAGCTACTG zinc finger, CCHC domain

ASSAY1093

Hs00226352 ml ZCCHC6 containing 6 AAAGGCTCTTCAGGTAGCCTTTCCA

Sfi1 homolog, spindle

ASSAY1094 assembly associated

Hs00289449 ml SFI 1 (yeast) GCAGAATGAGATGGCTGAGCGATTC

ASSAY1096 Hs00323180 ml ZNF862 zinc finger protein 862 TGGCATCCTTGGGACCTGCTGCTGC complement component

ASSAY 1097

Hs00704884 s1 C5AR1 5a receptor 1 TATTTA I I I I ATGGCAAGTTGGAAA

ASSAY1 101 mitochondrial GTPase 1

Hs00536591 g1 MTG1 homolog (S. cerevisiae) CCGAAAAGAGAACCTGGAGTACTGT

ASSAY1 102 RNF216L; ring finger protein 216-

Hs00415445 ml RNF216 like;ring finger protein 216 GAGTGGCGACTC I I I I GAAACAGAT Table 6: Informative probes for MCI versus non-MCI

Assays with p values <0.05 are marked with an asterisk.

Sequence No.

(DiaGenic TaqMan Gene Gene Context

probe ID) Assay ID Symbol name Sequence (Oligonucleotide sequence)

ASSAY001 1 glyceraldehyde-3-phosphate

Hs99999905 ml GAPDH dehydrogenase GGGCGCCTGGTCACCAGGGCTGCTT

ASSAY0012 interferon stimulated

Hs00158122 ml ISG20 exonuclease gene 20kDa GCATCCAGAACAGCCTGCTTGGACA small inducible cytokine

ASSAY0014 subfamily E, member 1

(endothelial monocyte-

Hs00171 131 ml SCYE1 activating) GATGCTTTCCCAGGAGAGCCTGACA

ASSAY0020 Hs00190266 ml STX4 syntaxin 4 AGTGGAGATGCAGGGGGAGATGATC chromosome 21 open reading

ASSAY0022

Hs00190463 ml C21 orf33 frame 33 GGGAAGCCCATCGGCTTGTGCTGCA

ASSAY0032* Ras association (RalGDS/AF-6)

Hs00200394 ml RASSF1 domain family member 1 GAGGTGAACTGGGACGCCTTCAGCA peter pan homolog

ASSAY0047* PPAN;PPAN- (Drosophila);PPAN-P2RY1 1

Hs00220301 ml P2RY1 1 readth rough ATCAACGTGCACAAGGTGAACCTGA chromosome 1 open reading

ASSAY0051

Hs00220527 ml C1 orf128 frame 128 CCCTCTGAGATGAGACTGTACAAGA pleckstrin homology domain

ASSAY0054 containing, family A

(phosphoinositide binding

Hs00221227 ml PLEKHA4 specific) member 4 TCTCCCCAGGACAGAGTGTCTGCTC sulfide quinone reductase-like

ASSAY0057

Hs00221859 ml SQRDL (yeast) GTTGAGCCCAGTGAGAGACATTTCT

ASSAY0070* Hs00225747 ml NOTCH2 Notch homolog 2 (Drosophila) GTGCCTTTACTGGCCGGCACTGTGA chromosome 2 open reading

ASSAY0072

Hs00225928 ml C2orf47 frame 47 AGGGAGCGAAGCAGGC I I I I GCTCA

ASSAY0082* Hs00228787 ml COASY Coenzyme A synthase AAAGATCTGTTGAAGAGCAAGTTGC

SWI/SNF related, matrix

ASSAY0089 associated, actin dependent

regulator of chromatin,

Hs00231324 ml SMARCA4 subfamily a, member 4 GAATCCTCACCAGGACCTGCAAGCG

ASSAY0093* low density lipoprotein receptor-

Hs00233856 ml LRP1 related protein 1 CCCCTGAGATTTGTCCACAGAGTAA

ADAM metallopeptidase

ASSAY0096*

Hs00234224 ml ADAM 17 domain 17 GGTGTCCAGTGCAGTGACAGGAACA

ASSAY01 10* Hs00157194 ml CTSB cathepsin B AAGCCACCCCAGAGAGTTATGTTTA

ASSAY01 13* general transcription factor ME,

Hs00157831 ml GTF2E2 polypeptide 2, beta 34kDa GCCCTTCTCACTCAGCATTATGGAT

ASSAY01 14* major histocompatibility

Hs00157950 ml HLA-DOB complex, class II, DO beta ACAGACTCTCCAGAAGA I I I I GTGA

ASSAY0123 Hs00160216 ml EXOSC10 exosome component 10 GTTGCTTCAGTGCATGAGCAGAGTA

ASSAY0126 Hs00162077 ml SOAT1 sterol O-acyltransferase 1 CCATCTTGCCAGGTGTGCTGATTCT

ASSAY0128 Bruton agammaglobulinemia

Hs00163761 ml BTK tyrosine kinase GTCAGGACTGAGCACACAGGTGAAC ASSAY0132 Hs00166580 ml UBE3A ubiquitin protein ligase E3A CTAGCCGAATGAAGCGAGCAGCTGC pinin, desmosome associated

ASSAY0135

HsOO-170192 ml PNN protein GGCAGTCAGTAGGCTGGGCGGGGAG

ASSAY0137* Hs99999908 ml GUSB glucuronidase, beta TGAACAGTCACCGACGAGAGTGCTG

ASSAY0139 Hs00173091 ml HMG20B high-mobility group 20B GAAAAGCAGCGGTACCTGGATGAGG

ASSAY0140 HsOO-173196 ml ZNF146 zinc finger protein 146 AGGATCTGCGCGGAAGAAGCCTGAG

ASSAY0144 Hs00174143 ml IFNG interferon, gamma AAGAAATA I I I I AATGCAGGTCATT

ASSAY0148* Hs00174575 ml CCL5 chemokine (C-C motif) ligand 5 CAACCCAGCAGTCGTCTTTGTCACC

ASSAY0161 Hs00176998 ml PRKCB protein kinase C, beta GGCAGAAATTTGAGAGGGCCAAGAT mitogen-activated protein

ASSAY0163

Hs00177066 ml MAPK1 kinase 1 CGGCATGGTGTGCTCTGCTTATGAT

ASSAY0178 Hs00186661 ml NCOA1 nuclear receptor coactivator 1 CACCTCAGCCACCCCTGAATGCTCA

ASSAY0179 RAB7, member RAS oncogene

Hs00187510 ml RAB7L1 family-like 1 CGGTGGGAGTGGA I I I I GCTCTGAA

ASSAY0181 Hs00188259 ml WARS tryptophanyl-tRNA synthetase AACCAAGGTCAATAAGCATGCGTTT

ASSAY0182* fibroblast growth factor (acidic)

Hs00188433 ml FIBP intracellular binding protein TGACCGGTTGGCCAGGGACTATGCA

ASSAY0184* bromodomain PHD finger

Hs00189461 ml BPTF transcription factor AGCAGCACTCCAGGTAGGCGAAAAC cold inducible RNA binding

ASSAY0190*

Hs00154457 ml CIRBP protein GCCCGACTCAGTGGCCGCCATGGCA transcription elongation factor B

ASSAY0193 (SIM), polypeptide 3 (1 10kDa,

Hs00162605 ml TCEB3 elongin A) TAGACATTCTTGCGGAGACTGGGGT src kinase associated

ASSAY0202

Hs00182698 ml SKAP2 phosphoprotein 2 CCTCTGATGGAGCCCAGTTTCCTCC

ASSAY0203 phosphodiesterase 4A, cAMP- specific (phosphodiesterase E2

Hs00183479 ml PDE4A dunce homolog, Drosophila) CCTGGCCCAAGAACTGGAGAACCTG

ASSAY0206 ubiquitination factor E4B (UFD2

Hs00195897 ml UBE4B homolog, yeast) AAATACCCCCTCATGGCACTAGGTG

ASSAY0207* granzyme A (granzyme 1 ,

cytotoxic T-lymphocyte-

Hs00196206 ml GZMA associated serine esterase 3) CCTGCTAATTCCTGAAGATGTCTGT

ASSAY0209 Hs00200082 ml UBL3 ubiquitin-like 3 CAATTGGCCAATGGACTGGGAAGAA

ASSAY021 1 CCR4-NOT transcription

Hs00203341 ml CNOT4 complex, subunit 4 GATAATTCCCAGCAGATATCTAACA chromosome 1 1 open reading

ASSAY0212

Hs00204260 ml C1 1 orf21 frame 21 GAGGAGGAGCGCTGTGCCCAGGTGG

ASSAY0216 Hs00209573 ml KIF13B kinesin family member 13B TGCCAACAGGAAGCGAGGCTCTCTT

SID1 transmembrane family,

ASSAY0217

Hs0021 1 141 ml SIDT2 member 2 GACCCGCAACAGGACAGAGGGCGTG

ASSAY0223* Hs00215938 ml RNF31 ring finger protein 31 TGCCCCACAACCGGATGCAGGCCCT

ASSAY0227 Hs00222984 ml HPS4 Hermansky-Pudlak syndrome 4 CATAGAGGAAGTGTACCACAGCAGC

DENN/MADD domain

ASSAY0228*

Hs00227687 ml DENND2D containing 2D TGGAAGAGGTCCTGCTGGTCAATCT tankyrase, TRF1 -interacting

ASSAY0230* ankyrin-related ADP-ribose

Hs00228829 ml TNKS2 polymerase 2 TGAAACAGCATTGCATTGTGCTGCT

ASSAY0236 Hs00266763 ml GSPT1 G1 to S phase transition 1 CCGTGCGGCACCTGTGGAATCCTCT

ASSAY0242 Hs00276830 ml RUNDC2A RUN domain containing 2A CAGTGAAACAGTGCCAGATCCGCTT neuroguidin, EIF4E binding

ASSAY0244*

Hs00295675 ml NGDN protein CTACAGAAAAGGGTCTCAGCTTCTT

DNAJC25-

ASSAY0253

Hs00374428 ml GNG10 DNAJC25-GNG10 readthrough TACGAGACACTCAAGGTCTCTCAGG

ASSAY0255 Hs00382970 ml PFDN5 prefoldin subunit 5 ATGAAACAGGCCGTCATGGAAATGA

ASSAY0257 DnaJ (Hsp40) homolog,

Hs00397335 ml DNAJC13 subfamily C, member 13 GGTCCAAAGGTTCGAATTACGTTAA chromosome 16 open reading

ASSAY0261 *

Hs00429212 ml C16orf35 frame 35 GCTGTGCAGGAGACCCAGCTCATCC

ASSAY0263* Hs00606262 g1 HDAC1 histone deacetylase 1 AGGAGAAGAAAGAAGTCACCGAAGA

ASSAY0264 Hs00606522 ml TARDBP TAR DNA binding protein GAGAAGTTCTTATGGTGCAGGTCAA

ASSAY0266 family with sequence similarity

Hs00607689 ml FAM103A1 103, member A1 AGGCAATCGGTTGCAAGACAACAGA

ASSAY0267 Hs00609831 g1 AARS alanyl-tRNA synthetase CGGCGCCTCAGCCAAGGCCCTGAAT

ASSAY0278 Hs01092416 s1 N/A N/A GTGTGAAGATCCAGCCTGATGCCCA

ASSAY0282* sel-1 suppressor of lin-12-like

Hs00192572 ml SEL1 L (C. elegans) CGGGAAACAAACATTCGAGATATGT

ASSAY0284 ATP-binding cassette, sub¬

Hs00194045 ml ABCA1 family A (ABC1 ), member 1 ACCCAATCCCAGACACGCCCTGCCA amyloid beta (A4) precursor

ASSAY0285 protein-binding, family A,

Hs00194072 ml APBA2 member 2 AACATTCCAGAGACAAAGAAGGTGG

LIM domain containing

ASSAY0286 preferred translocation partner

Hs00194400 ml LPP in lipoma GAGGACTTCCACAAGAAATTTGCCC

ASSAY0290 survival motor neuron domain

Hs00195343 ml SMNDC1 containing 1 GTGAAGATGGACAGTGTTATGAAGC

ASSAY0299 polymerase (RNA) III (DNA

Hs00197744 ml POLR3C directed) polypeptide C (62kD) CAGATAACAAGGAGCCCATTCCAGA

ASSAY0304 Hs00199030 ml EHD1 EH-domain containing 1 G G CTG G CC AAG G TTC AC G CCT AC AT

ASSAY0306 Hs00199344 ml ZFHX3 zinc finger homeobox 3 AGGGCGGAGCATCGTCCAGCCAAGC

ASSAY0313 nuclear cap binding protein

Hs00201247 ml NCBP2 subunit 2, 20kDa GACCAGCACTTCCGGGGTGACAATG

ASSAY0317 meningioma expressed antigen

Hs00201970 ml MGEA5 5 (hyaluronidase) GTGGAGGAAGCTGAGCAACTTATGA polymerase (DNA directed),

ASSAY0322*

Hs00203191 ml POLL lambda GATTGAGCAGACAGTCCAGAAAGCA

ASSAY0329 Hs00204383 ml COMMD9 COMM domain containing 9 AGAGCCTGCTCAAGGCCTCCTCGAA

ASSAY0332* staphylococcal nuclease and

Hs00205182 ml SND1 tudor domain containing 1 CAGCGAGAGGTGGAGGTGGAGGTGG

SEC24 family, member D (S.

ASSAY0335

Hs00207926 ml SEC24D cerevisiae) CAGCAAGCCAGCTTATTCTACCAGA

ASSAY0343 Hs0021 1070 ml ERGIC3 ERGIC and golgi 3 AGCGGCATGAGCTTGGGAAAGTCGA fission 1 (mitochondrial outer

ASSAY0346* membrane) homolog (S.

Hs0021 1420 ml FIS1 cerevisiae) CTGCTCGAGGAGCTGCTGCCCAAAG

ASSAY0348* Hs00212451 ml CAB39 calcium binding protein 39 GCTCATTGACTTTGAGGGCAAAAAA sirtuin (silent mating type

ASSAY0352 information regulation 2

Hs00213029 ml SIRT7 homolog) 7 (S. cerevisiae) AATCAGCACGGCAGCGTCTATCCCA

ASSAY0356* family with sequence similarity

Hs00214159 ml FAM46A 46, member A ACTC AC G CTC AAG GAAGCTTATGTG

ASSAY0359* Hs00214745 ml DPP8 dipeptidyl-peptidase 8 CTGCCTGCTCCAAGTGATTTCAAGT chromosome 19 open reading

ASSAY0366

Hs00215835 ml C19orf60 frame 60 CAGCAGCTGAAAATGAAGGTAATTA

ASSAY0370* Hs00217272 ml NUP133 nucleoporin 133kDa AAC I I I I AAAAGATGGCATTCAGCT

F-box and leucine-rich repeat

ASSAY0372*

Hs00218079 ml FBXL8 protein 8 CACAAAAATCAGTTGCGAATGTGAG

ASSAY0378 Hs00400987 ml DTX3 deltex homolog 3 (Drosophila) CTGACGAGAGCTGCATTTGGAAGTG

ASSAY0382 PEST proteolytic signal

Hs00706913 g1 PCNP containing nuclear protein AATGTAGGCAAACTATCAATTTTTT

ASSAY0393 Hs00295454 s1 N/A N/A AGCTAAGAGGTTTCCAGTGCAATAC

TRAF2 and NCK interacting

ASSAY0402

Hs00390635 ml TNIK kinase ACCCATCAGAGCAAGCAACCCTGAT

ASSAY0407* Hs00540709 s1 TMEM203 transmembrane protein 203 CGGGAGCTGGTGCAGTGGCTAGGCT

ASSAY0408* complement component (3b/4b)

Hs00559348 ml CR1 receptor 1 (Knops blood group) TGTTCCTGCTGCCTGCCCACATCCA

ASSAY0410 family with sequence similarity

Hs00607709 ml F AM 96 A 96, member A CACTCAACAGAAGAAGACATCAATA

ASSAY0421 * Hs00609836 ml AARS alanyl-tRNA synthetase CAAAATTTGGGGCTGGATGACACCA

ASSAY0425 PWP2 periodic tryptophan

Hs00610478 ml PWP2 protein homolog (yeast) GGCTGGCCAAGTACTTCTTCAATAA mitochondrial ribosomal protein

ASSAY0429*

Hs0061 1 133 ml MRPL10 L10 CGCTGCTAGGTGGCTGCATTGATGA

ASSAY0432 Hs00696974 ml BUD31 BUD31 homolog (S. cerevisiae) GAAAGCCATCAGCAGAGAACTCTAT

ASSAY0440 Hs00706419 s1 SELT selenoprotein T ACATGATTGAGAACCAGTGTATGTC

ASSAY0443* eukaryotic translation initiation

EIF5A; factor 5A;eukaryotic translation

Hs00739474 g1 EIF5AL1 initiation factor 5A-like 1 GAAGAGATCCTGATCACGGTGCTGT

ASSAY0445 Hs00740463 ml CSNK1A1 casein kinase 1 , alpha 1 GGCAAGGGCTAAAGGCTGCAACAAA chromosome 18 open reading

ASSAY0450*

Hs00743508 s1 C18orf32 frame 32 AGGTAGAA I I I I GGGAGGTAATAAT

ASSAY0451 Hs00745818 s1 ZNF595 zinc finger protein 595 CAAAGC I I I I AATCGGCCCTCAACC ubiquitin-conjugating enzyme

ASSAY0453*

Hs00748530 s1 UBE2L3 E2L 3 CTAAGATGCTGCGATCCCGTTCTGC

ASSAY0455* Hs00748915 s1 PFN1 profilin 1 TTTTTGGGCCATTACCCCATACCCC

ASSAY0456* Hs00750443 s1 ARL8B ADP-ribosylation factor-like 8B GTGTGACTCTGTGGGGACTGCATAG

ASSAY0458 glutamic-oxaloacetic

transaminase 2, mitochondrial

Hs00751057 s1 GOT2 (aspartate aminotransferase 2) GCTGATGCCGTACCCTCACCC I I I I

ASSAY0459 Hs00754648 s1 SFRS13A splicing factor, arginine/serine- TGATGCCAGCTGGGAAATTGAGTTT rich 13A

ASSAY0460 mitochondrial translational

Hs00759012 s1 MTRF1 L release factor 1 -like CGGACTAAGGATGCGGTCCCGGGTT

ASSAY0464* Hs00793391 ml CSNK1A1 casein kinase 1 , alpha 1 AG I I I I ATGTAAGGGGTTTCCTGCA

ASSAY0467 chaperonin containing TCP1 ,

Hs00798979 s1 CCT6A subunit 6A (zeta 1 ) TTTGGGATGTCAGCAGTGGCCTGAA

ASSAY0474* Hs00235003 ml PTGDR prostaglandin D2 receptor (DP) GCCCGTAATTTATCGCGCTTACTAT

TNF receptor-associated factor

ASSAY0477*

Hs00237035 ml TRAF3 3 TCGCGCTGCAGAAACACGAAGACAC tyrosine 3-

ASSAY0478 monooxygenase/tryptophan 5- monooxygenase activation

Hs00237047 ml YWHAZ protein, zeta polypeptide GATAAAAAGAACATCCAGTCATGGA synuclein, alpha (non A4

ASSAY0479* component of amyloid

Hs00240906 ml SNCA precursor) GTGGCAACAGTGGCTGAGAAGACCA hematopoietically expressed

ASSAY0480*

Hs00242160 ml HHEX homeobox ACCCCCTGGGCAAACCTCTACTCTG

ASSAY0481 lymphotoxin beta (TNF

Hs00242737 ml LTB superfamily, member 3) ATCAGGGAGGACTGGTAACGGAGAC methyl-CpG binding domain

ASSAY0482

Hs00242770 ml MBD1 protein 1 ATTACCAGAGCCCCACAGGAGACAG

ASSAY0483 cyclin-dependent kinase 5,

Hs00243655 s1 CDK5R1 regulatory subunit 1 (p35) CCGGAAGGCCACGCTGTTTGAGGAT

ASSAY0484* cell division cycle 25 homolog B

Hs00244740 ml CDC25B (S. pombe) GGCGGAGCAGACGTTTGAACAGGCC

LSM14B, SCD6 homolog B (S.

ASSAY0486

Hs00247895 s1 LSM14B cerevisiae) GAGCCTGGGATGAGCCCCGGCAGCG

UDP-N-acetyl-alpha-D-

ASSAY0502 galactosamine:polypeptide N- acetylgalactosaminyltransferase

Hs00257171 s1 GALNT10 10 (GalNAc-T10) AGATTCTGCACAAGTCAGCAGTGCA coenzyme Q10 homolog B (S.

ASSAY0504

Hs00257861 ml COQ10B cerevisiae) CGCCCGTGCGGAATGGCAGATATTT

ASSAY0512* ADP-ribosylation factor GTPase

Hs00260786 ml ARFGAP2 activating protein 2 GTATCCCGAAGCTCTGTCTCCCACT

ASSAY0516 histidine triad nucleotide binding

Hs00261620 ml HINT2 protein 2 GCGCGGGGGGCAGGTCCGAGGAGCT

ASSAY0523* Hs00264679 ml CST3 cystatin C CGCCCGCAAGCAGATCGTAGCTGGG

SWI/SNF related, matrix

ASSAY0534* associated, actin dependent

regulator of chromatin,

Hs00268265 ml SMARCC1 subfamily c, member 1 CCAAACTCCCTGCAAAGTGTTTCAT

ASSAY0538 Hs00269779 ml GGT5 gamma-glutamyltransferase 5 TCAGCCAGGAGGTGCAGAGGGGACT

ASSAY0540* small nuclear ribonucleoprotein

Hs00270536 ml SNRNP40 40kDa (U5) TGAGCCCATCATTATCTCAGCATCG

ASSAY0541 * Hs00270620 s1 IER2 immediate early response 2 CCCCGCCAAAGTCAGCCGCAAACGA ASSAY0543 eukaryotic translation initiation

Hs00272235 ml EIF3M factor 3, subunit M AGAAGAGTGATGCTGCTTCAAAAGT

ASSAY0544 CDC42 effector protein (Rho

Hs00272381 s1 CDC42EP3 GTPase binding) 3 ACTCCTCCAGCCTGTCCGAACAGTA zinc finger protein 36, C3H

ASSAY0546*

Hs00272828 ml ZFP36L2 type-like 2 GTCGACTTCTTGTGCAAGACAGAGA

ASSAY0551 hydroxysteroid (17-beta)

Hs00275054 ml HSD17B12 dehydrogenase 12 GTGGAAAGATCCAAAGGGGCTATTC

ASSAY0552 blocked early in transport 1

Hs00275374 s1 BET1 L homolog (S. cerevisiae)-like TCTCCATCCATGCTCACCATAGCCC

ASSAY0560* Hs00291823 ml ZMAT2 zinc finger, matrin type 2 AAAAGAAAGATGGAAAACCAGTGCA

ASSAY0563 intraflagellar transport 20

Hs00292725 ml IFT20 homolog (Chlamydomonas) GGGGCCGGCAGCCATGGCCAAGGAC

ASSAY0565* Hs00293336 ml TMEM129 transmembrane protein 129 TTTGACATCTGGAGCTGGAGGCCTG

ASSAY0566 Hs00293370 ml SPPL3 signal peptide peptidase 3 TATTTAAAGGGCGACCTCCGGCGGA solute carrier family 38,

ASSAY0568

Hs00298999 ml SLC38A10 member 10 TTCGCCTGCCAGTCCCAGGTGCTGC

ASSAY0572 proline, glutamate and leucine

Hs00300396 ml PELP1 rich protein 1 TCTCTCAAAGGCAAGCTGGCCTCAT

ASSAY0579* Hs00330066 ml CCNY cyclin Y CCGTCGTCACCCTGGTGTACCTTGA

ASSAY0585 Hs00358616 ml STK16 serine/threonine kinase 16 GTGAGCGGACTGATGTCTGGTCCCT cysteine-rich with EGF-like

ASSAY0588*

Hs00360923 g1 CRELD2 domains 2 TCCAAGTACGAGTCCAGCGAGATTC

ASSAY0593 SGT1 , suppressor of G2 allele

Hs00362511 g1 SUGT1 of SKP1 (S. cerevisiae) CTGCAACATCCCAGAGGTTTTTCCA leucine-rich alpha-2-

ASSAY0597

Hs00364835 ml LRG1 glyco protein 1 ACCAAAAAGCCCAGGGGGCATTCAA

RAB24, member RAS

ASSAY0599

Hs00365678 g1 RAB24 oncogene family GTATTTGGGACACAGCAGGCTCTGA phosphatidylinositol-3,4,5-

ASSAY0603* trisphosphate-dependent Rac

Hs00368207 ml PREX1 exchange factor 1 CTTCTTGCAGTCGGCATTCCTGCAT

ASSAY061 1 Hs00371424 s1 HIST1 H4D histone cluster 1 , H4d TTCGGCGGCTGAGCTTACCTCTACA

ASSAY0612* Hs00372401 g1 COMMD4 COMM domain containing 4 GGGACAGGGGATTGATTATGAGAAG

ASSAY0617 Hs00375440 ml TMEM168 transmembrane protein 168 CCCACCAACTTCTGCAGTCCTGATG

ASSAY0618 phosphatidylglycerophosphate

Hs00375485 ml PGS1 synthase 1 I I I I CGAGCTCATGAAGGGGCAGAT phosphatidylinositol-5-

ASSAY0619 phosphate 4-kinase, type II,

Hs00375556 ml PIP4K2C gamma CC I I I I CCACAGGGAAAATCTGCCC amyloid beta (A4) precursor

ASSAY0624 protein-binding, family B,

Hs00377427 ml APBB1 member 1 (Fe65) TCCCCAGAGGACACAGATTCCTTCT

ASSAY0625* ubiquitin protein ligase E3

Hs00378208 ml UBR4 component n-recognin 4 CACTTGCTTGG C AAG AC AC AAC ACT

ASSAY0627* Hs00378635 ml EXOSC8 exosome component 8 GCTGGGTTCAAAACCGTGGAACCTC

ASSAY0628* Hs00378772 ml KIAA0368 KIAA0368 GGAGACCCAACGTTGTTATCGTCAG chromosome 1 open reading

ASSAY0632

Hs00379295 ml C1 orf144 frame 144 AACCCATCCTCGACAGGCCAACCAG ASSAY0634 Hs00379889 ml PQLC3 PQ loop repeat containing 3 GACCTGGCCATGAATCTATGTACTT complement component 5a

ASSAY0637

Hs00383718 ml C5AR1 receptor 1 AGACCAGAACATGAACTCCTTCAAT

ASSAY0638 prolyl-tRNA synthetase 2,

Hs00384448 ml PARS2 mitochondrial (putative) GGCTGGGATTGCGGTGCCTGTGCTT

ASSAY0641 * F-box and WD repeat domain

Hs00385203 g1 FBXW5 containing 5 CCTGTCGCCCGACAACAGGTACCTG

ASSAY0645* mitogen-activated protein

Hs00387426 ml MAP2K4 kinase kinase 4 CAAATAATGGCAGTTAAAAGAATTC

SEC16 homolog A (S.

ASSAY0648*

Hs00389570 ml SEC16A cerevisiae) AACCTAAGAAGGGTGAATCCTGGTT

ASSAY0653 Hs00393297 ml ZNF512B zinc finger protein 512B TGGTAAGAAAAGGGCTGCGGACAGC

ASSAY0654 fizzy/cell division cycle 20

Hs00393592 ml FZR1 related 1 (Drosophila) ACGATGCCACGCGTCACAGAGATGC

ASSAY0656 Hs00395045 ml STMN3 stathmin-like 3 CCAGTACGGGGACATGGAGGTGAAG

ASSAY0657* protein phosphatase 1 ,

Hs00397738 ml PPP1 R3E regulatory (inhibitor) subunit 3E GGGGAGTGATGACAGAAGGGATGGA

ASSAY0660 Hs00402617 ml MPZL3 myelin protein zero-like 3 GTGCCTGGATTCAGACTATGAAGAG

ASSAY0665 DnaJ (Hsp40) homolog,

Hs00406064 ml DNAJC2 subfamily C, member 2 TCAAAGCAGCTCATAAAGCAATGGT

ASSAY0672* melanoma inhibitory activity

Hs00412706 ml Ml A3 family, member 3 AGTGAATTTGGATCAGTGGACGGGC

ASSAY0676 Hs00414732 g1 LSMD1 LSM domain containing 1 AGCCGTCGGATTCCTTCTCTGCCGG

ASSAY0677 Hs00414889 ml ANKRD36B ankyrin repeat domain 36B GAAGGAAAGGACTGCCCTACATTTG

ASSAY0683 small nucleolar RNA host gene

Hs00417251 ml SNHG6 6 (non-protein coding) TAGCTGGGCTCTGCGAGGTGCAAGA

ASSAY0684 Hs00417273 ml LRRK2 leucine-rich repeat kinase 2 TTTGGCCCTCCTCACTGAGACTATT structural maintenance of

ASSAY0686 chromosomes flexible hinge

Hs00418955 ml SMCHD1 domain containing 1 AAGGA I I I I AAATGGACAGGAACAG

ASSAY0697 Hs00428488 g1 PRDX2 peroxiredoxin 2 CCTTTGCCCACGCAGCTTTCAGTCA

ASSAY0710* Hs00536891 ml ITSN2 intersectin 2 GCTATGAATGGAGGGCCAAACATGT chromosome 5 open reading

ASSAY0713

Hs00538077 ml C5orf41 frame 41 ACACCCACAGACAGCATCGCACAGA

ASSAY0714* Hs00538879 s1 LUC7L3 LUC7-like 3 (S. cerevisiae) GTTACACTCAATGCAATTCTCAAGT chromosome 10 open reading

ASSAY0715*

Hs00539341 ml C10orf137 frame 137 AGACTAGTGAGCAAATCTGTGTCTG

ASSAY0719 Hs00540753 ml DYNLL2 dynein, light chain, LC8-type 2 GCCTCCGTGAAGTGTCACACCATGT coiled-coil domain containing

ASSAY0720*

Hs00540812 ml CCDC101 101 AGAGGCTGAGTGCAACATCCTTCGG

F-box and leucine-rich repeat

ASSAY0723

Hs00542109 ml FBXL16 protein 16 ACGGACGCAGGCCTCGAGGTTATGC chromosome 14 open reading

ASSAY0728

Hs00544515 s1 C14orf139 frame 139 CCAGGGGACGGGAGCAGGTACCCAC nuclear import 7 homolog (S.

ASSAY0733

Hs00602949 g1 NIP7 cerevisiae) TGTACTATGTGAGTGAGAAGATTAT eukaryotic translation initiation

ASSAY0736

Hs00603727 g1 EIF1 factor 1 TTAAGAAAAAGTTTGCCTGCAATGG

ASSAY0739 Hs00606808 ml MRPS6 mitochondrial ribosomal protein ACAACAGAGGCGGGTATTTCTTGGT S6

ASSAY0741 tumor necrosis factor receptor

Hs00606874 g1 TNFRSF13C superfamily, member 13C CGGAGACAAGGACGCCCCAGAGCCC

ASSAY0743 karyopherin alpha 2 (RAG

Hs00818252 g1 KPNA2 cohort 1 , importin alpha 1 ) TCATCTTTAGCATGTGGCTACTTAC

ASSAY0746 transmembrane and coiled-coil

Hs00828573 ml TMCC1 domain family 1 CCGGGACATCCAGGAGGCCCTGGAG

ASSAY0748* Hs00830558 g1 FOXN3 forkhead box N3 TCTAGGGACTTGGTGTTGCTTGGAA

ASSAY0752 Hs00854645 g1 BRI3 brain protein I3 CCTTCCTGGGCATCTTCCTGGCCAT

ASSAY0753 Hs00855332 g1 LDHA lactate dehydrogenase A TCTGACGCACCACTGCCAATGCTGT

ASSAY0754 deleted in lymphocytic leukemia

Hs00867656 s1 DLEU2 2 (non-protein coding) AAAAATTTA I I I I ACACATGTCAAG

ASSAY0756 Hs00894392 ml TBX21 T-box 21 ACAATGTGACCCAGATGATTGTGCT

ASSAY0760 CCCTC-binding factor (zinc

Hs00902008 ml CTCF finger protein) AGAACCAGCCAACAGCTATCATTCA

ASSAY0780 Hs00942554 ml RPL6 ribosomal protein L6 TCTTGCAAGATGGCGGGTGAAAAAG

ASSAY0781 Hs00943178 g1 PGK1 phosphoglycerate kinase 1 AGCCCACAGCTCCATGGTAGGAGTC

ASSAY0797* Bruton agammaglobulinemia

Hs00975865 ml BTK tyrosine kinase TTATCCCTTCCAGGTTGTATATGAT

ASSAY0798 ER degradation enhancer,

Hs00976004 ml EDEM1 mannosidase alpha-like 1 CAACTCCAGCTCCAACTGCAATCGT

ASSAY0799* Hs00982887 g1 BCL2L12 BCL2-like 12 (proline rich) CCGCCCAGCCCAGAATTACAGGGTC

ASSAY0802* granzyme A (granzyme 1 ,

cytotoxic T-lymphocyte-

Hs00989184 ml GZMA associated serine esterase 3) ACTCGTGCAATGGAGATTCTGGAAG erythrocyte membrane protein

ASSAY0805

Hs00996794 ml EPB42 band 4.2 GAGAGGAGCTACAGATTCCGTTCAG transforming growth factor, beta

ASSAY0807*

Hs00998133 ml TGFB1 1 ACAGCAAGGTCCTGGCCCTGTACAA

ASSAY0810 Hs01007839 ml TNP01 transports 1 GAAGCTGCCTGCAGTGCCTTTGCTA

ASSAY0814* glutamate-ammonia ligase

Hs01013056 g1 GLUL (glutamine synthetase) TCTGAAGTACATCGAGGAGGCCATT

Rho GTPase activating protein

ASSAY0819

Hs01030693 ml ARHGAP17 17 CCAAGATAGTAACAGACTCCAATTC

ASSAY0826 Hs01036536 ml BCR breakpoint cluster region ATTGCTGTGGTCACCAAGAGAGAGA

ASSAY0827 Hs01037385 s1 HMGB1 high-mobility group box 1 AAAG C AAAG G G AG G ATAAA AC AGTA

ASSAY0831 Hs01043735 ml ECE1 endothelin converting enzyme 1 GCGGCCTATCGGGCTTACCAGAACT zinc finger and BTB domain

ASSAY0834*

Hs01053201 s1 ZBTB38 containing 38 GTAATAAGCTGTGTGACGGTCTTTA

ASSAY0836 Hs01053867 s1 NCRNA00203 non-protein coding RNA 203 AGCGCCAGTGCTGGCATGGGCTTTC

ASSAY0844* tetratricopeptide repeat and

Hs01064792 ml TRANK1 ankyrin repeat containing 1 TAAAGAAGG AAG GTATTGTTCAG G A

ASSAY0846* Hs01065498 ml PIM1 pim-1 oncogene CAGAGGGTCTCTTCAGAATGTCAGC transcription factor A,

ASSAY0854

Hs01082775 ml TFAM mitochondrial GGTGATTCACCGCAGGAAAAGCTGA ASSAY0856 serine threonine kinase 39

Hs01085351 ml STK39 (STE20/SPS1 homolog, yeast) TAAGTTGGCTTCTGGCTGTGATGGG acetylcholinesterase (Yt blood

ASSAY0857*

Hs01085739 g1 ACHE group) CTGCAGGTGCTGGTGGGTGTGGTGA

ASSAY0858 maternally expressed 3 (non¬

Hs01087966 ml MEG3 protein coding) GGATCCCTCACCCGGGTCTCTCCTC

ASSAY0861 * HsO-1093019 ml GSPT1 G1 to S phase transition 1 CAGAGAAACTTGGTACTTGTCTTGG ribose 5-phosphate isomerase

ASSAY0865*

Hs01 107136 ml RPIA A GTGATCGCTGATTTCAGGAAAGATT

ASSAY0871 * transforming growth factor, beta

Hs01 1 14250 ml TGFBR3 receptor III TCTATT CT CAC AC AG G G G AG AC AG C zinc finger, DHHC-type

ASSAY0876*

Hs01372307 ml ZDHHC18 containing 18 ACCTCCCAGCCTAATTGACCGGAGG

ASSAY0882* myxovirus (influenza virus)

Hs01550808 ml MX2 resistance 2 (mouse) GAATGCCTACTTCTTGGAAACCAGC

ASSAY0886 Hs01564142 ml GLIPR1 GLI pathogenesis-related 1 CTATACATGACTTGGGACCCAGCAC presenilin 2 (Alzheimer disease

ASSAY0888*

Hs01577197 ml PSEN2 4) CCTCATTGGCTTGTGTCTGACCCTC

ASSAY0893* Hs01591359 s1 N/A N/A AGTGCCCTTTAGATGATTCCCCCTC

ASSAY0894 ubiquitin-conjugating enzyme

Hs01592406 ml UBE2F E2F (putative) AACATTAAAGGATGTCGTTTGGGGA

ASSAY0900* Hs01636043 s1 SRP9 signal recognition particle 9kDa TGCTGTTGTGACCAATAAATATAAA

ASSAY0914 olfactory receptor, family 52,

Hs023391 16 s1 OR52K1 subfamily K, member 1 GGCAGTTCTCCAGCTTGCCTCTCAG

ASSAY0916 Hs02339727 ml ZNF708 zinc finger protein 708 CAAACCCCCAGCTATGTGTTCTCAT

ASSAY0923 tumor necrosis factor, alpha-

Hs02621508 s1 TNFAIP8 induced protein 8 AAATACAGATGTCTCCAGACCTGAG

PRELI domain containing

1 ;similar to Px19-like protein

(25 kDa protein of relevant

ASSAY0924

PRELID1 ; evolutionary and lymphoid

LOC728666; interest) (PRELI);PX19 protein

Hs02638995 g1 LOC388955 pseudogene CGCCCGGCTGATGGTGGTGGAGGAA

ASSAY0925 guanine nucleotide binding

Hs02863396 ml GNA12 protein (G protein) alpha 12 AGCGAGTTTCAGCTGGGGGAGTCGG cytochrome b-245, alpha

ASSAY0929

Hs03044361 ml CYBA polypeptide ATCTCCTGCTCTCGGTGCCCGCCGG

ASSAY0933 Hs99999148 ml CCL4 chemokine (C-C motif) ligand 4 TCCAGCGCTCTCAGCACCAATGGGC

ASSAY0934 colony stimulating factor 2

Hs00929873 ml CSF2 (granulocyte-macrophage) CAGAAATGTTTGACCTCCAGGAGCC

ASSAY0936 Hs00245438 ml MVP major vault protein GGCCTACAACTGGCACTTTGAGGTG

ASSAY0941 Hs00328784 s1 MTMR3 myotubularin related protein 3 CCCTCGGGAAGGTTGGTATTGAGGG translocase of outer

ASSAY0944* mitochondrial membrane 40

Hs01587378 mH TOMM40 homolog (yeast) CCCACAGAGGCGTTCCCTGTACTGG

ASSAY0950 Hs01 123468 ml DID01 death inducer-obliterator 1 ATGCGGTGCTCAGGCAGGTATTAAA chromosome 19 open reading

ASSAY0951

Hs00293472 ml C19orf36 frame 36 ATCGAAAGCCGCATCGACTGTCAGC ASSAY0962* dehydrogenase/reductase

Hs0021 1306 ml DHRS7 (SDR family) member 7 CTTTAAGAGTGGTGTGGATGCAGAC zinc finger and BTB domain

ASSAY0970

Hs00210321 ml ZBTB20 containing 20 TGAAACTACTGAAGAAACCCAAGAC

DENN/MADD domain

ASSAY0980

Hs00400648 ml DENND4A containing 4A AGAACTATGCAATGGAGGTTCTCAT

ASSAY0982 Hs00171488 ml SLIT1 slit homolog 1 (Drosophila) ACCGAGCGCCTGGAACTCAATGGCA

ASSAY0996 Hs00369838 s1 GPR82 G protein-coupled receptor 82 ATGGGAATATCAATCTGCTCAATGC

ASSAY0998 transmembrane BAX inhibitor

Hs00162661 ml TMBIM6 motif containing 6 CACTCATTTCATTCAGGCTGGCCTG

ASSAY1000 family with sequence similarity

Hs00403541 ml FAM129C 129, member C CTGCCCTGAATCCTTGGGAGACCAT

ASSAY1001 metallophosphoesterase

Hs00155586 ml MPPED1 domain containing 1 AGTGGCTGGGCAGCCTGCCCTACGA low density lipoprotein receptor-

AS SAY 1004 related protein 8, apolipoprotein

Hs00182998 ml LRP8 e receptor GGACGACTGCCCCAAGAAGACCTGT

ASSAY1010* Hs00394748 ml AGRN agrin GAGTTCTGTGTGGAAGATAAACCCG

ASSAY1025 myeloid differentiation primary

Hs00182082 ml MYD88 response gene (88) CCCAGCATTGAGGAGGATTGCCAAA spectrin, beta, non-erythrocytic

ASSAY1026

Hs00162271 ml SPTBN1 1 GCTCTGGGCACACAGGTGAGGCAGC

ASSAY1030 aldehyde dehydrogenase 2

Hs00355914 ml ALDH2 family (mitochondrial) AAATGTCTCCGGTATTATGCCGGCT

ASSAY1036 DCP1 decapping enzyme

Hs00218198 ml DCP1A homolog A (S. cerevisiae) CCATCCCGGTTGCAGGCGCCCCACT

ASSAY1042* Hs00202482 ml ACOT9 acyl-CoA thioesterase 9 CTGAAAATAAAGGGCCGGCATTTGT

AS SAY 1048 Hs00174752 ml EPHB4 EPH receptor B4 GACCCAACTGGATGAGAGCGAGGGC leucine rich repeat containing

ASSAY1056

Hs00698399 ml LRRC50 50 TGCCCGATTTGCGTGTACTGAATTT

YKT6 v-SNARE homolog (S.

ASSAY1064*

Hs00559914 ml YKT6 cerevisiae) TATAAAACTGCCCGGAAACAAAACT dihydropyrimidine

ASSAY1083

Hs00559278 ml DPYD dehydrogenase TCATGGACAAGAAACTGCCAAGTTT

ASSAY1084* ubiquitin protein ligase E3

Hs00390223 ml UBR4 component n-recognin 4 ACATGACCACAGGTACAGAATCAGA

ASSAY1088* glutamate-ammonia ligase

Hs00374213 ml GLUL (glutamine synthetase) TTTCTGTGGCTGGGAACACCTTCCA

ASSAY1096* Hs00323180 ml ZNF862 zinc finger protein 862 TGGCATCCTTGGGACCTGCTGCTGC

ASSAY"! 100* Hs00186918 ml SNX3 sorting nexin 3 AAAGAGAGAGCAAGGTCGTAGTTCC

ASSAY^"! 101 * mitochondrial GTPase 1

Hs00536591 g1 MTG1 homolog (S. cerevisiae) CCGAAAAGAGAACCTGGAGTACTGT

5-nucleotidase domain

AS S AY 1 104

Hs00261330 s1 NT5DC1 containing 1 CATATCGATGCATGCAATGGAAAGA Table 7: Informative probes for Prodromal AD versus Progressed AD (All probes have p-value <0.5)

Sequence No.

(DiaGenic Assay Gene Gene Context

Assay ID) ID Symbol name Sequence (Oligonucleotide sequence)

glyceraldehyde-3-phosphate

ASSAY001 1

Hs99999905 ml GAPDH dehydrogenase GGGCGCCTGGTCACCAGGGCTGCTT interferon stimulated

ASSAY0012

Hs00158122 ml ISG20 exonuclease gene 20kDa GCATCCAGAACAGCCTGCTTGGACA chromosome 21 open reading

ASSAY0022

Hs00190463 ml C21 orf33 frame 33 GGGAAGCCCATCGGCTTGTGCTGCA

ASSAY0038 Hs00218782 ml RNF1 14 ring finger protein 1 14 TGCCCTGCGGACACGTCTTTTGCTC chromosome 1 open reading

ASSAY0041

Hs00219523 ml C1 orf183 frame 183 TCAAACAGGAGCTGATGTCCATGAA solute carrier family 44,

ASSAY0052

Hs00220814 ml SLC44A2 member 2 AAACGAGAACAAACCCTATCTGTTT sulfide quinone reductase-like

ASSAY0057

Hs00221859 ml SQRDL (yeast) GTTGAGCCCAGTGAGAGACATTTCT

ASSAY0082 Hs00228787 ml COASY Coenzyme A synthase AAAGATCTGTTGAAGAGCAAGTTGC low density lipoprotein

ASSAY0093

Hs00233856 ml LRP1 receptor-related protein 1 CCCCTGAGATTTGTCCACAGAGTAA

ADAM metallopeptidase

ASSAY0096

Hs00234224 ml ADAM 17 domain 17 GGTGTCCAGTGCAGTGACAGGAACA

ADAM metallopeptidase

ASSAY0099

Hs00153853 ml ADAM 10 domain 10 AAACAGTGCAGTCCAAGTCAAGGTC general transcription factor HE,

ASSAY01 13

Hs00157831 ml GTF2E2 polypeptide 2, beta 34kDa GCCCTTCTCACTCAGCATTATGGAT major histocompatibility

ASSAY01 14

Hs00157950 ml HLA-DOB complex, class II, DO beta ACAGACTCTCCAGAAGA I I I I GTGA phospholipase D1 ,

ASSAY0122

Hs001601 18 ml PLD1 phosphatidylcholine-specific CTT AAACG AAAAG C AC AAC AAG GAG

Bruton agammaglobulinemia

ASSAY0128

Hs00163761 ml BTK tyrosine kinase GTCAGGACTGAGCACACAGGTGAAC pinin, desmosome associated

ASSAY0135

Hs00170192 ml PNN protein GGCAGTCAGTAGGCTGGGCGGGGAG

ASSAY0140 Hs00173196 ml ZNF146 zinc finger protein 146 AGGATCTGCGCGGAAGAAGCCTGAG

ASSAY0148 Hs00174575 ml CCL5 chemokine (C-C motif) ligand 5 CAACCCAGCAGTCGTCTTTGTCACC

ASSAY0181 Hs00188259 ml WARS tryptophanyl-tRNA synthetase AACCAAGGTCAATAAGCATGCGTTT bromodomain PHD finger

ASSAY0184

Hs00189461 ml BPTF transcription factor AGCAGCACTCCAGGTAGGCGAAAAC

NADH dehydrogenase

(ubiquinone) Fe-S protein 3,

ASSAY0189

30kDa (NADH-coenzyme Q

Hs00190028 ml NDUFS3 reductase) CGACACGCGCCCCACTGTCAGACCA granzyme A (granzyme 1 ,

ASSAY0207 cytotoxic T-lymphocyte-

Hs00196206 ml GZMA associated serine esterase 3) CCTGCTAATTCCTGAAGATGTCTGT

ASSAY0209 Hs00200082 ml UBL3 ubiquitin-like 3 CAATTGGCCAATGGACTGGGAAGAA coiled-coil domain containing

ASSAY0210

Hs00203291 ml CCDC106 106 CTCGGATGGAGGCAGAGGACCACTG

ASSAY0216 Hs00209573 ml KIF13B kinesin family member 13B TGCCAACAGGAAGCGAGGCTCTCTT

ASSAY0223 Hs00215938 ml RNF31 ring finger protein 31 TGCCCCACAACCGGATGCAGGCCCT tankyrase, TRF1 -interacting

ASSAY0230 ankyrin-related ADP-ribose

Hs00228829 ml TNKS2 polymerase 2 TGAAACAGCATTGCATTGTGCTGCT

ASSAY0234 Hs00266026 ml IGFBP7 insulin-like growth factor GCACCTGCGAGCAAGGTCCTTCCAT binding protein 7

ASSAY0242 Hs00276830 ml RUNDC2A RUN domain containing 2A CAGTGAAACAGTGCCAGATCCGCTT

ASSAY0263 Hs00606262 g1 HDAC1 histone deacetylase 1 AGGAGAAGAAAGAAGTCACCGAAGA family with sequence similarity

ASSAY0266

Hs00607689 ml FAM103A1 103, member A1 AGGCAATCGGTTGCAAGACAACAGA

Wilms tumor 1 associated

ASSAY0281

Hs00191727 ml WTAP protein CTTCTGCCTGGAGAGGATTCAAGAT sel-1 suppressor of lin-12-like

ASSAY0282

Hs00192572 ml SEL1 L (C. elegans) CGGGAAACAAACATTCGAGATATGT

5, 10-

ASSAY0291 methylenetetrahydrofolate

Hs00195560 ml MTHFR reductase (NADPH) GTGGCAGGTTACCCCAAAGGCCACC

ASSAY0304 Hs00199030 ml EHD1 EH-domain containing 1 G G CTG G CC AAG G TTC AC G CCT AC AT

ASSAY0306 Hs00199344 ml ZFHX3 zinc finger homeobox 3 AGGGCGGAGCATCGTCCAGCCAAGC

ASSAY0324 Hs00203316 ml HOOK2 hook homolog 2 (Drosophila) AGCGGCGGCAGGTGCAGGAACTGCA staphylococcal nuclease and

ASSAY0332

Hs00205182 ml SND1 tudor domain containing 1 CAGCGAGAGGTGGAGGTGGAGGTGG fission 1 (mitochondrial outer

ASSAY0346 membrane) homolog (S.

Hs0021 1420 ml FIS1 cerevisiae) CTGCTCGAGGAGCTGCTGCCCAAAG

ASSAY0348 Hs00212451 ml CAB39 calcium binding protein 39 GCTCATTGACTTTGAGGG C AAAAAA family with sequence similarity

ASSAY0356

Hs00214159 ml FAM46A 46, member A ACTCACGCTCAAGGAAGCTTATGTG

ASSAY0359 Hs00214745 ml DPP8 dipeptidyl-peptidase 8 CTGCCTGCTCCAAGTGATTTCAAGT

ASSAY0370 Hs00217272 ml NUP133 nucleoporin 133kDa AAC I I I I AAAAGATGGCATTCAGCT

F-box and leucine-rich repeat

ASSAY0372

Hs00218079 ml FBXL8 protein 8 CACAAAAATCAGTTGCGAATGTGAG

ArfGAP with dual PH domains

ASSAY0373

Hs00218203 ml ADAP2 2 ACGACTGCCTGGTCTTAAAGGAACA

PEST proteolytic signal

ASSAY0382

Hs00706913 g1 PCNP containing nuclear protein AATGTAGGCAAACTATCAATTTTTT acyl-CoA synthetase short-

ASSAY0392

Hs00287264 ml ACSS1 chain family member 1 TGGGGTCAGTGGGAGAGCCCATCAA

TRAF2 and NCK interacting

ASSAY0402

Hs00390635 ml TNIK kinase ACCCATCAGAGCAAGCAACCCTGAT

ASSAY0405 Hs00415453 g1 TRA@ T cell receptor alpha locus TGGATTCAGTTGGCATGGGTGAGCA

ASSAY0407 Hs00540709 s1 TMEM203 transmembrane protein 203 CGGGAGCTGGTGCAGTGGCTAGGCT saccharopine dehydrogenase

ASSAY0417

Hs00608534 ml SCCPDH (putative) CCTAAGGCGGGCGGGGTCTTCACAC

BUD31 homolog (S.

ASSAY0432

Hs00696974 ml BUD31 cerevisiae) GAAAGCCATCAGCAGAGAACTCTAT chromosome 18 open reading

ASSAY0450

Hs00743508 s1 C18orf32 frame 32 AGGTAGAA I I I I G G G AG G T AATAAT

ASSAY0451 Hs00745818 s1 ZNF595 zinc finger protein 595 CAAAGC I I I I AATCGGCCCTCAACC ubiquitin-conjugating enzyme

ASSAY0453

Hs00748530 s1 UBE2L3 E2L 3 CTAAGATGCTGCGATCCCGTTCTGC

ASSAY0455 Hs00748915 s1 PFN1 profilin 1 TTTTTGGGCCATTACCCCATACCCC

ASSAY0456 Hs00750443 s1 ARL8B ADP-ribosylation factor-like 8B GTGTGACTCTGTGGGGACTGCATAG

ASSAY0464 Hs00793391 ml CSNK1A1 casein kinase 1 , alpha 1 AG I I I I ATGTAAGGGGTTTCCTGCA chaperonin containing TCP1 ,

ASSAY0467

Hs00798979 s1 CCT6A subunit 6A (zeta 1 ) TTTGGGATGTCAGCAGTGGCCTGAA integrin, beta 1 (fibronectin

ASSAY0476 receptor, beta polypeptide,

Hs00236976 ml ITGB1 antigen CD29 includes MDF2, TGTGGCGCGTGCAGGTGCAATGAAG MSK12)

TNF receptor-associated factor

ASSAY0477

Hs00237035 ml TRAF3 3 TCGCGCTGCAGAAACACGAAGACAC tyrosine 3- monooxygenase/tryptophan 5-

ASSAY0478

monooxygenase activation

Hs00237047 ml YWHAZ protein, zeta polypeptide GATAAAAAGAACATCCAGTCATGGA hematopoietically expressed

ASSAY0480

Hs00242160 ml HHEX homeobox ACCCCCTGGGCAAACCTCTACTCTG methyl-CpG binding domain

ASSAY0482

Hs00242770 ml MBD1 protein 1 ATTACCAGAGCCCCACAGGAGACAG cell division cycle 25 homolog

ASSAY0484

Hs00244740 ml CDC25B B (S. pombe) GGCGGAGCAGACGTTTGAACAGGCC

G protein-coupled receptor

ASSAY0487

Hs00248078 ml GPR162 162 AGGATGGAGATGACGATGGGGGCTG

ASSAY0488 Hs00248163 ml GLS glutaminase ACTTCTACTTCCAGCTGTGCTCCAT

ASSAY0491 Hs00250236 s1 KIF21 B kinesin family member 21 B CCCAACATCCATGAGACACCCCGAG

Wolf-Hirschhorn syndrome

ASSAY0500

Hs00256558 ml WHSC1 L1 candidate 1 -like 1 TTACAGAAAGGTGCCAGCGAGATTT coenzyme Q10 homolog B (S.

ASSAY0504

Hs00257861 ml COQ10B cerevisiae) CGCCCGTGCGGAATGGCAGATATTT

ADP-ribosylation factor

ASSAY0512

Hs00260786 ml ARFGAP2 GTPase activating protein 2 GTATCCCGAAGCTCTGTCTCCCACT

ASSAY0531 Hs00267008 ml IP05 importin 5 TGCTTGCCAGATGTTGGTTTGCTAT small nuclear

ASSAY0540

Hs00270536 ml SNRNP40 ribonucleoprotein 40kDa (U5) TGAGCCCATCATTATCTCAGCATCG

ASSAY0541 Hs00270620 s1 IER2 immediate early response 2 CCCCGCCAAAGTCAGCCGCAAACGA eukaryotic translation initiation

ASSAY0543

Hs00272235 ml EIF3M factor 3, subunit M AGAAGAGTGATGCTGCTTCAAAAGT

ASSAY0547 Hs00272902 s1 RNF1 13A ring finger protein 1 13A GGGGCCAAGTGCAACCCAGGCAGCC spectrin repeat containing,

ASSAY0576

Hs00326979 ml SYNE1 nuclear envelope 1 CAAGCTCGAGGCTCTATTATCAGTC

ASSAY0579 Hs00330066 ml CCNY cyclin Y CCGTCGTCACCCTGGTGTACCTTGA

CSE1 chromosome

ASSAY0582

Hs00354853 ml CSE1 L segregation 1 -like (yeast) AGGAACTGGAGAATTGTTGAAGATG cysteine-rich with EGF-like

ASSAY0588

Hs00360923 g1 CRELD2 domains 2 TCCAAGTACGAGTCCAGCGAGATTC splicing factor, arginine/serine-

ASSAY0604

Hs00369090 ml SFRS18 rich 18 ACCAACAGGATCCAAGCCAGATTGA phosphatidylinositol-5-

ASSAY0619 phosphate 4-kinase, type II,

Hs00375556 ml PIP4K2C gamma CC I I I I CCACAGGGAAAATCTGCCC chromosome 1 open reading

ASSAY0632

Hs00379295 ml C1 orf144 frame 144 AACCCATCCTCGACAGGCCAACCAG complement component 5a

ASSAY0637

Hs00383718 ml C5AR1 receptor 1 AGACCAGAACATGAACTCCTTCAAT

F-box and WD repeat domain

ASSAY0641

Hs00385203 g1 FBXW5 containing 5 CCTGTCGCCCGACAACAGGTACCTG mitogen-activated protein

ASSAY0645

Hs00387426 ml MAP2K4 kinase kinase 4 CAAATAATGGCAGTTAAAAGAATTC

ASSAY0656 Hs00395045 ml STMN3 stathmin-like 3 CCAGTACGGGGACATGGAGGTGAAG

ATG16 autophagy related 16-

ASSAY0659

Hs00400565 ml ATG16L2 like 2 (S. cerevisiae) GCTGGTGCCGGCCTATAACCATCTC

ASSAY0660 Hs00402617 ml MPZL3 myelin protein zero-like 3 GTGCCTGGATTCAGACTATGAAGAG

DnaJ (Hsp40) homolog,

ASSAY0665

Hs00406064 ml DNAJC2 subfamily C, member 2 TCAAAGCAGCTCATAAAGCAATGGT

ASSAY0667 Hs00409956 g1 GPS2 G protein pathway suppressor CTCCGACTCATCCTCTCTGCGCCCC 2

melanoma inhibitory activity

ASSAY0672

Hs00412706 ml Ml A3 family, member 3 AGTGAATTTGGATCAGTGGACGGGC

ASSAY0676 Hs00414732 g1 LSMD1 LSM domain containing 1 AGCCGTCGGATTCCTTCTCTGCCGG

ASSAY0677 Hs00414889 ml ANKRD36B ankyrin repeat domain 36B GAAGGAAAGGACTGCCCTACATTTG membrane-associated ring

ASSAY0678

Hs00415203 ml MARCH3 finger (C3HC4) 3 GCCACCCAGAGCCCCTTCAATGACC

ASSAY0684 Hs00417273 ml LRRK2 leucine-rich repeat kinase 2 TTTGGCCCTCCTCACTGAGACTATT structural maintenance of

ASSAY0686 chromosomes flexible hinge

Hs00418955 ml SMCHD1 domain containing 1 AAGGA I I I I AAATGGACAGGAACAG

NADH dehydrogenase

(ubiquinone) 1 beta

ASSAY0696

NDUFB8;SEC subcomplex, 8, 19kDa;SEC31

Hs00428204 ml 31 B homolog B (S. cerevisiae) CGGATGATGGCATGGGGTATGGCGA

ASSAY0704 Hs00430663 g1 UBL5 ubiquitin-like 5 CTGGGGGACTATGAAATCCACGATG mitochondrial GTPase 1

ASSAY0709

Hs00536594 ml MTG1 homolog (S. cerevisiae) CAGCGCTTTGGGTACGTGCAGCACT

ASSAY0710 Hs00536891 ml ITSN2 intersectin 2 GCTATGAATGGAGGGCCAAACATGT tumor necrosis factor, alpha-

ASSAY0712

Hs00537038 ml TNFAIP8L1 induced protein 8-like 1 TGCTTCGAGAGTAGGCCATGGACAC chromosome 5 open reading

ASSAY0713

Hs00538077 ml C5orf41 frame 41 ACACCCACAGACAGCATCGCACAGA

ASSAY0714 Hs00538879 s1 LUC7L3 LUC7-like 3 (S. cerevisiae) GTTACACTCAATGCAATTCTCAAGT chromosome 10 open reading

ASSAY0715

Hs00539341 ml C10orf137 frame 137 AGACTAGTGAGCAAATCTGTGTCTG advanced glycosylation end

ASSAY0724

Hs00542592 g1 AGER product-specific receptor CGCCGAGGAGAGGAGAGGAAGGCCC

ASSAY0726 Hs00543883 s1 HIST1 H4C histone cluster 1 , H4c TATGGCTTCGGCGGCTGAATCTAAG eukaryotic translation initiation

ASSAY0736

Hs00603727 g1 EIF1 factor 1 TTAAGAAAAAGTTTGCCTGCAATGG tumor necrosis factor receptor

ASSAY0741

Hs00606874 g1 TNFRSF13C superfamily, member 13C CGGAGACAAGGACGCCCCAGAGCCC karyopherin alpha 2 (RAG

ASSAY0743

Hs00818252 g1 KPNA2 cohort 1 , importin alpha 1 ) TCATCTTTAGCATGTGGCTACTTAC

ASSAY0748 Hs00830558 g1 FOXN3 forkhead box N3 TCTAGGGACTTGGTGTTGCTTGGAA mitogen-activated protein

ASSAY0749

Hs00833126 g1 MAPK6 kinase 6 CTGAGCCTTGTTGGCAATACTCAGA

ASSAY0753 Hs00855332 g1 LDHA lactate dehydrogenase A TCTGACGCACCACTGCCAATGCTGT

ASSAY0780 Hs00942554 ml RPL6 ribosomal protein L6 TCTTGCAAGATGGCGGGTGAAAAAG

Bruton agammaglobulinemia

ASSAY0797

Hs00975865 ml BTK tyrosine kinase TTATCCCTTCCAG GTTGTATATG AT granzyme A (granzyme 1 ,

ASSAY0802 cytotoxic T-lymphocyte-

Hs00989184 ml GZMA associated serine esterase 3) ACTCGTGCAATGGAGATTCTGGAAG transforming growth factor,

ASSAY0807

Hs00998133 ml TGFB1 beta 1 ACAGCAAGGTCCTGGCCCTGTACAA

ASSAY0810 Hs01007839 ml TNP01 transportin 1 GAAGCTGCCTGCAGTGCCTTTGCTA glutamate-ammonia ligase

ASSAY0814

Hs01013056 g1 GLUL (glutamine synthetase) TCTGAAGTACATCGAGGAGGCCATT

ASSAY0818 Hs01018736 g1 UBL3 ubiquitin-like 3 GCCAAACTCTCAAGGTCAGAGGAAT

Rho GTPase activating protein

ASSAY0819

Hs01030693 ml ARHGAP17 17 CCAAGATAGTAACAGACTCCAATTC actin related protein 2/3

ASSAY0820

Hs01031740 ml ARPC2 complex, subunit 2, 34kDa TGAAAACAATCACGGGGAAGACGTT ASSAY0827 Hs01037385 s1 HMGB1 high-mobility group box 1 AAAGCAAAGGGAGGATAAAACAGTA zinc finger and BTB domain

ASSAY0834

Hs01053201 s1 ZBTB38 containing 38 GTAATAAGCTGTGTGACGGTCTTTA

ASSAY0836 Hs01053867 s1 NCRNA00203 non-protein coding RNA 203 AGCGCCAGTGCTGGCATGGGCTTTC tetratricopeptide repeat and

ASSAY0844

Hs01064792 ml TRANK1 ankyrin repeat containing 1 TAAAG AAGG AAG GTATTGTTCAG G A transcription factor A,

ASSAY0854

Hs01082775 ml TFAM mitochondrial GGTGATTCACCGCAGGAAAAGCTGA serine threonine kinase 39

ASSAY0856

Hs01085351 ml STK39 (STE20/SPS1 homolog, yeast) TAAGTTGGCTTCTGGCTGTGATGGG maternally expressed 3 (non¬

ASSAY0858

Hs01087966 ml MEG3 protein coding) GGATCCCTCACCCGGGTCTCTCCTC transforming growth factor,

ASSAY0871

Hs01 1 14250 ml TGFBR3 beta receptor III TCTATTCTCACACAGGGGAGACAGC presenilin 2 (Alzheimer

ASSAY0888

Hs01577197 ml PSEN2 disease 4) CCTCATTGGCTTGTGTCTGACCCTC signal recognition particle

ASSAY0900

Hs01636043 s1 SRP9 9kDa TGCTGTTGTGACCAATAAATATAAA

ASSAY0916 Hs02339727 ml ZNF708 zinc finger protein 708 CAAACCCCCAG CTATGTGTTCTCAT tumor necrosis factor, alpha-

ASSAY0923

Hs02621508 s1 TNFAIP8 induced protein 8 AAATACAGATGTCTCCAGACCTGAG

ASSAY0959 Hs00185574 ml EZR ezrin AAAATGCCGAAACCAATCAATGTCC dehydrogenase/reductase

ASSAY0962

Hs0021 1306 ml DHRS7 (SDR family) member 7 CTTTAAGAGTGGTGTGGATGCAGAC

ASSAY0966 Hs00323799 ml RNF160 ring finger protein 160 TGAAAAGGCATGTCCTAGTTCAGAT suppressor of Ty 16 homolog

ASSAY0988

Hs00200446 ml SUPT16H (S. cerevisiae) AGGAAATTACATACCGAGCATCAAA

ASSAY0996 Hs00369838 s1 GPR82 G protein-coupled receptor 82 ATGGGAATATCAATCTGCTCAATGC family with sequence similarity

ASSAY1000

Hs00403541 ml FAM129C 129, member C CTGCCCTGAATCCTTGGGAGACCAT membrane-spanning 4-

ASSAY1066 domains, subfamily A, member

Hs00544818 ml MS4A1 1 TCTCTGTTCTTGGGCA I I I I GTCAG

ASSAY1071 Hs00358603 g1 APOL1 apolipoprotein L, 1 AGGAAGCTGGAGCGAGGGTGCAACA cysteine-rich with EGF-like

ASSAY"! 087

Hs00360928 ml CRELD2 domains 2 GTGCGAAGATGTGGACGAGTGCTCA integrin, beta 1 (fibronectin

receptor, beta polypeptide,

ASSAY1095

antigen CD29 includes MDF2,

Hs00559595 ml ITGB1 MSK12) TTGCTCAAACAGATGAAAATAGATG

Table 8: Informative probes for Very Mild versus Mild dementia (All probes have p- value <0.5)

Sequence No.

(DiaGenic Assay Gene Gene Context

Assay ID) ID Symbol name Sequence (Oligonucleotide sequence)

ASSAY001 1 glyceraldehyde-3-phosphate

Hs99999905 ml GAPDH dehydrogenase GGGCGCCTGGTCACCAGGGCTGCTT chromosome 21 open reading

ASSAY0022

Hs00190463 ml C21 orf33 frame 33 GGGAAGCCCATCGGCTTGTGCTGCA peter pan homolog

ASSAY0047 PPAN; (Drosophila);PPAN-P2RY1 1

Hs00220301 ml PPAN-P2RY1 1 readth rough ATCAACGTGCACAAGGTGAACCTGA chromosome 1 open reading

ASSAY0051

Hs00220527 ml C1 orf128 frame 128 CCCTCTGAGATGAGACTGTACAAGA solute carrier family 44,

ASSAY0052

Hs00220814 ml SLC44A2 member 2 AAACGAGAACAAACCCTATCTGTTT sulfide quinone reductase-like

ASSAY0057

Hs00221859 ml SQRDL (yeast) GTTGAGCCCAGTGAGAGACATTTCT

PAP associated domain

ASSAY0062

Hs00223727 ml PAPD5 containing 5 TTTACAACCAGGTAACGATGTTGGA

ASSAY0082 Hs00228787 ml COASY Coenzyme A synthase AAAGATCTGTTGAAGAGCAAGTTGC

ASSAY01 13 general transcription factor ME,

Hs00157831 ml GTF2E2 polypeptide 2, beta 34kDa GCCCTTCTCACTCAGCATTATGGAT

ASSAY0137 Hs99999908 ml GUSB glucuronidase, beta TGAACAGTCACCGACGAGAGTGCTG

ASSAY0150 Hs00174705 ml CD163 CD163 molecule ACCTGCTCAGCCCACAGGGAACCCA

NEDD8 activating enzyme E1

ASSAY01 2

Hs00182671 ml NAE1 subunit 1 GACCGGCAGCTGAGGTTGTGGGGTG

ASSAY0185 FRG1 ; FSHD region gene 1 ;FSHD

Hs00189530 ml FRG1 B region gene 1 family, member B TTCAAAATGGGAAAATGGCTTTGTT

ASSAY0187 hydroxysteroid (17-beta)

Hs00189576 ml HSD17B10 dehydrogenase 10 CGCCCCAGCCGACGTGACCTCTGAG lysine (K)-specific demethylase

ASSAY0205

Hs00188277 ml KDM5C 5C CCACCCGCGGACTGGCAGCCACCCT

ASSAY0209 Hs00200082 ml UBL3 ubiquitin-like 3 CAATTGGCCAATGGACTGGGAAGAA chromosome 1 1 open reading

ASSAY0212

Hs00204260 ml C1 1 orf21 frame 21 GAGGAGGAGCGCTGTGCCCAGGTGG

ASSAY0224 Hs00218060 ml TMEM106B transmembrane protein 106B GCGCCCCGCGTGCCGACATGGGAAA chromosome 16 open reading

ASSAY0261

Hs00429212 ml C16orf35 frame 35 GCTGTGCAGGAGACCCAGCTCATCC

ASSAY0279 Hs01585413 g1 N/A N/A TTTACCAAATTCAAGGTGGATGAAT amyloid beta (A4) precursor

ASSAY0285 protein-binding, family A,

Hs00194072 ml APBA2 member 2 AACATTCCAGAGACAAAGAAGGTGG

ASSAY0289 actin related protein 2/3

Hs00194815 ml ARPC1 B complex, subunit 1 B, 41 kDa CGCGGGAGGAGCCAAGCCGCCATGG

ASSAY0304 Hs00199030 ml EHD1 EH-domain containing 1 GGCTGGCCAAGGTTCACGCCTACAT

ASSAY0306 Hs00199344 ml ZFHX3 zinc finger homeobox 3 AGGGCGGAGCATCGTCCAGCCAAGC

ASSAY0307 Hs00199894 ml CD160 CD160 molecule GGCCCTTCAAGCTTTGTAAGCCTTG

ASSAY0327 bromodomain adjacent to zinc

Hs00203782 ml BAZ2A finger domain, 2A AGAAACTGGAGGCCCAAGAAACATT fission 1 (mitochondrial outer

ASSAY0346 membrane) homolog (S.

Hs00211420 ml FIS1 cerevisiae) CTGCTCGAGGAGCTGCTGCCCAAAG

F-box and leucine-rich repeat

ASSAY0372

Hs00218079 ml FBXL8 protein 8 CACAAAAATCAGTTGCGAATGTGAG thyroid hormone receptor

ASSAY0399

Hs00377979 ml TRIP6 interactor 6 GGACTTTCACAGGAAGTTTGCCCCA rhomboid, veinlet-like 1

ASSAY0422

Hs00610210 g1 RHBDL1 (Drosophila) TCTTGCCCAGATCATCGTGTTCCTG aurora kinase A interacting

ASSAY0428

Hs00610917 g1 AURKAIP1 protein 1 CTGAGACGCAAGCAGATCAAGTTCG

ASSAY0456 Hs00750443 s1 ARL8B ADP-ribosylation factor-like 8B GTGTGACTCTGTGGGGACTGCATAG

ASSAY0458 glutamic-oxaloacetic

transaminase 2, mitochondrial

Hs00751057 s1 GOT2 (aspartate aminotransferase 2) GCTGATGCCGTACCCTCACCC I I I I

ASSAY0463 Hs00762481 s1 RPL36 ribosomal protein L36 CCTTCTCCCCGTCGCTGTCCGCAGC

ASSAY0467 chaperonin containing TCP1 ,

Hs00798979 s1 CCT6A subunit 6A (zeta 1 ) TTTGGGATGTCAGCAGTGGCCTGAA

ASSAY0481 lymphotoxin beta (TNF

Hs00242737 ml LTB superfamily, member 3) ATCAGGGAGGACTGGTAACGGAGAC

ASSAY0489 Hs00248408 ml Sep6 septin 6 AGAAAGAGCTGCACGAGAAGTTTGA

UDP-N-acetyl-alpha-D-

ASSAY0502 galactosamine:polypeptide N- acetylgalactosaminyltransferase

Hs00257171 s1 GALNT10 10 (GalNAc-T10) AGATTCTGCACAAGTCAGCAGTGCA fermitin family homolog 3

ASSAY0507

Hs00258828 ml FERMT3 (Drosophila) GGATCCCAAGACAGACCCCGTGCGG

ASSAY0511 vacuolar protein sorting 25

Hs00260613 ml VPS25 homolog (S. cerevisiae) GAGGATGAGGAGTTCCACGGGCTGG κ ¾J ^ ^'^Ό ¾3 ¾ i! melanocortin 1 receptor (alpha

melanocyte stimulating

Hs00267168 s1 MC1 R hormone receptor) GCAGGACGCTCAAGGAGGTGCTGAC

ASSAY0537 Hs00269247 s1 GPR65 G protein-coupled receptor 65 TTCTCTCCTGCCTTGTGCAAAGGGA heat shock 70kDa protein

ASSAY0542 HSPA1 B; 1 B;heat shock 70kDa protein

Hs00271244 s1 HSPA1A 1A AGGACTTTGCTGCTG I I I I CCTATG

ASSAY0547 Hs00272902 s1 RNF113A ring finger protein 113A GGGGCCAAGTGCAACCCAGGCAGCC glycogen synthase kinase 3

ASSAY0553

Hs00275656 ml GSK3B beta AGAAATAATCAAGGTCCTGGGAACT ribosomal protein L32

ASSAY0570

Hs00299189 ml RPL32P3 pseudogene 3 AAGGAAGAGGACCAGGCTTCCTGTC chemokine (C-C motif) receptor

ASSAY0584

Hs00356601 ml CCR2 2 GCCACAAGCTGAACAGAGAAAGTGG

ASSAY0615 transmembrane emp24 protein

Hs00375047 ml TMED9 transport domain containing 9 CCCAGAGGACAAGGTCATCCTGGCC phosphatidylinositol-5-

ASSAY0619 phosphate 4-kinase, type II,

Hs00375556 ml PIP4K2C gamma CCTTTTCCACAGGGAAAATCTGCCC translocase of outer

ASSAY0621 mitochondrial membrane 40

Hs00375641 ml TOMM40L homolog (yeast)-like GCTCAGTCCCACTGAGGTGTTCCCC ASSAY0634 Hs00379889 ml PQLC3 PQ loop repeat containing 3 GACCTGGCCATGAATCTATGTACTT

F-box and WD repeat domain

ASSAY0641

Hs00385203 g1 FBXW5 containing 5 CCTGTCGCCCGACAACAGGTACCTG

ASSAY0667 Hs00409956 g1 GPS2 G protein pathway suppressor 2 CTCCGACTCATCCTCTCTGCGCCCC

ASSAY0676 Hs00414732 g1 LSMD1 LSM domain containing 1 AGCCGTCGGATTCCTTCTCTGCCGG

ASSAY0678 membrane-associated ring

Hs00415203 ml MARCH3 finger (C3HC4) 3 GCCACCCAGAGCCCCTTCAATGACC inscuteable homolog

ASSAY0682

Hs00416940 ml INSC (Drosophila) TGGCCTGCCTGGCTGCTCTGCGTAG

ASSAY0683 small nucleolar RNA host gene

Hs00417251 ml SNHG6 6 (non-protein coding) TAGCTGGGCTCTGCGAGGTGCAAGA

ASSAY0729 Hs00559804 ml CAPN1 calpain 1 , (mu/l) large subunit AAACTACCCAGCCACCTTCTGGGTG

ASSAY0741 tumor necrosis factor receptor

Hs00606874 g1 TNFRSF13C superfamily, member 13C CGGAGACAAGGACGCCCCAGAGCCC

ASSAY0743 karyopherin alpha 2 (RAG

Hs00818252 g1 KPNA2 cohort 1 , importin alpha 1 ) TC ATCTTT AG CATGTGGCTACTTAC protein-kinase, interferon-

ASSAY0751 inducible double stranded RNA

dependent inhibitor, repressor

Hs00852410 g1 PRKRIR of (P58 repressor) TACTCTGCAGTGCAGTGTCAGATTT

ASSAY0753 Hs00855332 g1 LDHA lactate dehydrogenase A TCTGACGCACCACTGCCAATGCTGT

ASSAY0797 Bruton agammaglobulinemia

Hs00975865 ml BTK tyrosine kinase TTATCCCTTCCAG GTTGTATATG AT cold inducible RNA binding

ASSAY0804

Hs00989762 g1 CIRBP protein CTATAGCAGCCGGAGTCAGAGTGGT

ASSAY0814 glutamate-ammonia ligase

Hs01013056 g1 GLUL (glutamine synthetase) TCTGAAGTACATCGAGGAGGCCATT

ASSAY0820 actin related protein 2/3

Hs01031740 ml ARPC2 complex, subunit 2, 34kDa TGAAAACAATCACGGGGAAGACGTT

ASSAY0826 Hs01036536 ml BCR breakpoint cluster region ATTGCTGTGGTCACCAAGAGAGAGA

ASSAY0836 Hs01053867 s1 NCRNA00203 non-protein coding RNA 203 AGCGCCAGTGCTGGCATGGGCTTTC

ASSAY0844 tetratricopeptide repeat and

Hs01064792 ml TRANK1 ankyrin repeat containing 1 TAAAG AAGG AAG GTATTGTTCAG G A

ASSAY0856 serine threonine kinase 39

Hs01085351 ml STK39 (STE20/SPS1 homolog, yeast) TAAGTTGGCTTCTGGCTGTGATGGG

ASSAY0871 transforming growth factor, beta

Hs01 1 14250 ml TGFBR3 receptor III TCT ATTCTC AC AC AG G G G AG AC AG C presenilin 2 (Alzheimer disease

ASSAY0888

Hs01577197 ml PSEN2 4) CCTCATTGGCTTGTGTCTGACCCTC

ASSAY0914 olfactory receptor, family 52,

Hs023391 16 s1 OR52K1 subfamily K, member 1 GGCAGTTCTCCAGCTTGCCTCTCAG

ASSAY0916 Hs02339727 ml ZNF708 zinc finger protein 708 CAAACCCCCAG CTATGTGTTCTCAT

ASSAY0925 guanine nucleotide binding

Hs02863396 ml GNA12 protein (G protein) alpha 12 AGCGAGTTTCAGCTGGGGGAGTCGG

ASSAY0941 Hs00328784 s1 MTMR3 myotubularin related protein 3 CCCTCGGGAAGGTTGGTATTGAGGG

ASSAY0947 Hs00254569 s1 HRH2 histamine receptor H2 GGTCACCCCAGTTCGGGTCGCCATC ASSAY0976 Hs00376366 ml CCDC12 coiled-coil domain containing 12 CAAACCGGTTGCAGTGGAGGAGAAG chromosome 13 open reading

ASSAY"! 014

Hs00204129 ml C13orf15 frame 15 TCG G AG AGTG CAG ATTCACTTTATA

ASSAY1023 inositol 1 ,4,5-triphosphate

Hs01573555 ml ITPR3 receptor, type 3 GCTTCATCTGTGGTCTGGAGAGGGA spectrin, beta, non-erythrocytic

ASSAY1026

Hs00162271 ml SPTBN1 1 GCTCTGGGCACACAGGTGAGGCAGC

ASSAY1035 solute carrier family 39 (zinc

Hs00202392 ml SLC39A6 transporter), member 6 CGGAGACGAAGGCGCAATGGCGAGG

Table 9: Informative probes for Prospective modelling (non-clear versus clear

progression of AD)

Assays with p values <0.05 are marked with an asterisk.

pleckstrin homology domain

containing, family A

ASSAY0054

(phosphoinositide binding

Hs00221227 ml PLEKHA4 specific) member 4 TCTCCCCAGGACAGAGTGTCTGCTC

ASSAY0055* Hs00221499 ml KAT2A K(lysine) acetyltransferase 2A TCACTTCCCCAAATTCCTGTCCATG sulfide quinone reductase-like

ASSAY0057*

Hs00221859 ml SQRDL (yeast) GTTGAGCCCAGTGAGAGACATTTCT endoplasmic reticulum

ASSAY0061

Hs00223525 ml ERAP2 aminopeptidase 2 AGCTAGTTGGTGCAGGGAGACTGAC

CREB regulated transcription

ASSAY0065

Hs00224328 ml CRTC3 coactivator 3 TACCTCCCAGATGGTGTCCTCAGAC

ASSAY0070 Hs00225747 ml NOTCH2 Notch homolog 2 (Drosophila) GTGCCTTTACTGGCCGGCACTGTGA

ASSAY0080 Hs00228549 ml SIK3 SIK family kinase 3 CCCAGCAGAGAGCCTGTCATAGGGA anterior pharynx defective 1

ASSAY0085

Hs00229911 ml APH1 B homolog B (C. elegans) TCATCGCCGGAGCTTTCTTCTGGTT

SWI/SNF related, matrix

associated, actin dependent

ASSAY0089*

regulator of chromatin,

Hs00231324 ml SMARCA4 subfamily a, member 4 GAATCCTCACCAGGACCTGCAAGCG low density lipoprotein

ASSAY0093

Hs00233856 ml LRP1 receptor-related protein 1 CCCCTGAGATTTGTCCACAGAGTAA

ADAM metallopeptidase

ASSAY0096*

Hs00234224 ml ADAM 17 domain 17 GGTGTCCAGTGCAGTGACAGGAACA ubiquitin-conjugating enzyme

ASSAY0097* E2D 1 (UBC4/5 homolog,

Hs00234280 ml UBE2D1 yeast) GAGGATTCAGAAAGAATTGAGTGAT membrane metallo-

ASSAY0098*

Hs00153519 ml MME endopeptidase TCC AG G C AATTTC AG G ATT ATTG G G

ASSAY0108 Hs00156251 ml CAPN2 calpain 2, (m/ll) large subunit GAAGCGCCCCACGGAGATCTGCGCT epoxide hydrolase 2,

ASSAY01 12

Hs00157403 ml EPHX2 cytoplasmic ACGTGACAGTAAAGCCCAGGGTCCG interleukin 1 receptor

ASSAY01 15*

Hs00158057 ml IL1 RAP accessory protein AACCA I I I I AGATGGAAAAGAGTAT

ASSAY01 19* Hs00159537 ml NBN nibrin CCCGGCAGGAGGAGAACCATACAGA nardilysin (N-arginine dibasic

ASSAY0120*

Hs00159668 ml NRD1 convertase) TG TC AC AAG C AC AG A ATCT ATG GAT

ASSAY0127* Hs00162394 ml STIM1 stromal interaction molecule 1 TTGTCCATGCAGTCCCCTAGCCTGC

ASSAY0132* Hs00166580 ml UBE3A ubiquitin protein ligase E3A CTAGCCGAATGAAGCGAGCAGCTGC superoxide dismutase 2,

ASSAY0133*

Hs00167309 ml SOD2 mitochondrial GGAACAACAGGCCTTATTCCACTGC

DnaJ (Hsp40) homolog,

ASSAY0136*

Hs00170600 ml DNAJA3 subfamily A, member 3 TCAACGTGACGATCCCCCCTGGGAC

ASSAY0137* Hs99999908 ml GUSB glucuronidase, beta TGAACAGTCACCGACGAGAGTGCTG colony stimulating factor 1

ASSAY0145

Hs00174164 ml CSF1 (macrophage) AGAGCATGACAAGGCCTGCGTCCGA

ASSAY0150 Hs00174705 ml CD163 CD163 molecule ACCTGCTCAGCCCACAGGGAACCCA

ASSAY0154* Hs00175407 ml CTSS cathepsin S TGTGAAAAACAGCTGGGGCCACAAC

ASSAY0156* Hs00175573 ml AQP9 aquaporin 9 CATCTTGATTGTCCTTGGATGTGGC

ASSAY0157* Hs00175591 ml PRNP prion protein CACGACCGAGGCAGAGCAGTCATTA inositol 1 ,4,5-trisphosphate 3-

ASSAY0158*

Hs00176666 ml ITPKB kinase B GCAAGATGGGAATCAGGACCTACCT

ASSAY0162* Hs00177028 ml PKN1 protein kinase N1 TGGCAGCACCAAGGACCGGAAGCTG mitogen-activated protein

ASSAY0163*

Hs00177066 ml MAPK1 kinase 1 CGGCATGGTGTGCTCTGCTTATGAT

ASSAY0166 Hs00178787 ml CDC42BPB CDC42 binding protein kinase CTGTCGCCTGTAGTTGCAGCCCCAC beta (DMPK-like)

3-ketodihydrosphingosine

ASSAY0169*

Hs00179997 ml KDSR reductase GCTCCAGCAGGTGGTCACCATGGGC

ASSAY0170 Hs00180965 ml ERBB2IP erbb2 interacting protein GCCGAAAGAATGTTGGCTCAATTAA

ASSAY0180 Hs00187845 ml BCL2A1 BCL2-related protein A1 AAAACGGAGGCTGGGAAAATGGCTT fibroblast growth factor (acidic)

ASSAY0182

Hs00188433 ml FIBP intracellular binding protein TGACCGGTTGGCCAGGGACTATGCA

BCL2-associated athanogene

ASSAY0183

Hs00188713 ml BAG 3 3 GGGCCCCAAGGAGACTCCATCCTCT cold inducible RNA binding

ASSAY0190

Hs00154457 ml CIRBP protein GCCCGACTCAGTGGCCGCCATGGCA growth factor receptor-bound

ASSAY0191

Hs00157817 ml GRB2 protein 2 GGGGGGACATCCTCAAGG I I I I GAA cytochrome b-245, alpha

ASSAY0194*

Hs00164370 ml CYBA polypeptide GGCCTGATCCTCATCACCGGGGGCA

S100 calcium binding protein

ASSAY0197

Hs00170953 ml S100A6 A6 CCCTACCGCTCCAAGCCCAGCCCTC

ASSAY0199 Hs00175295 ml TCF12 transcription factor 12 GCGCTTGATCCCTTGCAAGCAAAAA phosphodiesterase 4A, cAMP- specific (phosphodiesterase

ASSAY0203*

E2 dunce homolog,

Hs00183479 ml PDE4A Drosophila) CCTGGCCCAAGAACTGGAGAACCTG

Treacher Collins-Franceschetti

ASSAY0204*

Hs00184390 ml TCOF1 syndrome 1 GCATCTCCAGCACAGGTGAAAACCT coiled-coil domain containing

ASSAY0210

Hs00203291 ml CCDC106 106 CTCGGATGGAGGCAGAGGACCACTG

POZ (BTB) and AT hook

ASSAY0213*

Hs00204880 ml PATZ1 containing zinc finger 1 ACAAGTGTCAGACCTGCAATGCTTC family with sequence similarity

ASSAY0214*

Hs00207230 ml FAM38A 38, member A CGGCCCTGTGCATTGATTATCCCTG

ASSAY0215* Hs00208212 ml RBM19 RNA binding motif protein 19 ACGAGCCACTAAGCCAGCCGTGACA baculoviral IAP repeat-

ASSAY0218

Hs00212288 ml BIRC6 containing 6 (apollon) GCGAATGCATTCAGGAGCAAGAAGA

ASSAY0223 Hs00215938 ml RNF31 ring finger protein 31 TGCCCCACAACCGGATGCAGGCCCT

Hermansky-Pudlak syndrome

ASSAY0227*

Hs00222984 ml HPS4 4 CATAGAGGAAGTGTACCACAGCAGC

DENN/MADD domain

ASSAY0228*

Hs00227687 ml DENND2D containing 2D TGGAAGAGGTCCTGCTGGTCAATCT glucose-fructose

ASSAY0232 oxidoreductase domain

Hs00255879 ml GFOD1 containing 1 AAACCCTAGGCATCGGCAAGAACGT

ASSAY0242 Hs00276830 ml RUNDC2A RUN domain containing 2A CAGTGAAACAGTGCCAGATCCGCTT

ASSAY0246 Hs00330168 ml DNHD1 dynein heavy chain domain 1 GGGCGCTGGAGTCAAGTGACTCTAA

ASSAY0249 Hs00356977 ml PLEC plectin TGCAGGATGCCCAGGACGAGAAGGA scribbled homolog

ASSAY0250*

Hs00363005 ml SCRIB (Drosophila) ACGGAGAACCTGCTGATGGCCCTGC

GOLGA8B;GO golgin A8 family, member

ASSAY0251

Hs00367259 ml LGA8A B;golgin A8 family, member A AGAAGCCGGATGGGTTCTCGAGCCG

ASSAY0254* Hs00382453 ml XP05 exportin 5 TTGCGCTTATAAGAACCCACAATAC

ASSAY0267* Hs00609831 g1 AARS alanyl-tRNA synthetase CGGCGCCTCAGCCAAGGCCCTGAAT protein tyrosine phosphatase

ASSAY0270

Hs00754750 s1 PTP4A2 type IVA, member 2 CC I I I I CCCCCGATCCAAGTTGTAG phosphatidylethanolamine

ASSAY0272

Hs00831506 g1 PEBP1 binding protein 1 TGGCAAATTCAAGGTGGCGTCCTTC

Wilms tumor 1 associated

ASSAY0281

Hs00191727 ml WTAP protein CTTCTGCCTGGAGAGGATTCAAGAT amyloid beta (A4) precursor

ASSAY0285 protein-binding, family A,

Hs00194072 ml APBA2 member 2 AACATTCCAGAGACAAAGAAGGTGG

LIM domain containing

ASSAY0286 preferred translocation partner

Hs00194400 ml LPP in lipoma GAGGACTTCCACAAGAAATTTGCCC

5, 10-

ASSAY0291 * methylenetetrahydrofolate

Hs00195560 ml MTHFR reductase (NADPH) GTGGCAGGTTACCCCAAAGGCCACC

ASSAY0294* HsOO-196191 ml CD7 CD7 molecule TGGCGAGGACACAGATAAAGAAACT nuclear receptor co-repressor

ASSAY0296*

Hs00196955 ml NCOR2 2 GCGCCGAGCTGGCCTCCATGGAGCT transcription elongation

ASSAY0302

Hs00198676 ml TCERG1 regulator 1 TACTCCATGGTGTGTCGTTTGGACT

NADH dehydrogenase

ASSAY0309* (ubiquinone) flavoprotein 1 ,

Hs00200073 ml NDUFV1 51 kDa CGGCGACACGACAGCACCCAAGAAA nuclear cap binding protein

ASSAY0313*

Hs00201247 ml NCBP2 subunit 2, 20kDa GACCAGCACTTCCGGGGTGACAATG

ASSAY0319 Hs00202185 ml FTSJ1 FtsJ homolog 1 (E. coli) CTTAACCCATTACGCTGGCAAACTG staphylococcal nuclease and

ASSAY0332*

Hs00205182 ml SND1 tudor domain containing 1 CAGCGAGAGGTGGAGGTGGAGGTGG chromosome 17 open reading

ASSAY0338

Hs00209768 ml C17orf81 frame 81 GATATCAACAATCGGCTGGTTTACC abhydrolase domain

ASSAY0339*

Hs00209887 ml ABHD14A containing 14A GCCCTTGACCTTCCAGG I I I I GGGA

ASSAY0343* Hs0021 1070 ml ERGIC3 ERGIC and golgi 3 AGCGGCATGAGCTTGGGAAAGTCGA

Smg-6 homolog, nonsense

ASSAY0355 mediated mRNA decay factor

Hs00214019 ml SMG6 (C. elegans) CCCCTCATCGTGATCAATGAGCTGG

ASSAY0358* Hs00214624 ml TMEM214 transmembrane protein 214 TCCTTCCAGGCCTCCCTTACTGGCC

BTB (POZ) domain containing

ASSAY0361 *

Hs00215064 ml BTBD2 2 TCGCTGCAGGTCCCGCACAGTCGGG

ASSAY0364 Hs00215334 ml INTS8 integrator complex subunit 8 AAATGAGGCTTCCTGATATTCCTCT zinc finger protein 64 homolog

ASSAY0369*

Hs00217022 ml ZFP64 (mouse) AGACAATCACAGTTTCAGCTCCAGA

TBC1 domain family, member

ASSAY0374

Hs00218284 ml TBC1 D2 2 CTTCTGACGAAGTGCGCCTACCTCC

FK506 binding protein 2,

ASSAY0376*

Hs00234404 ml FKBP2 13kDa CACTACACGGGGAAGCTGGAAGATG

ASSAY0380* Hs00609603 ml ACVR2B activin A receptor, type MB ATTGCCCACAGGGACTTTAAAAGTA zinc finger, CCHC domain

ASSAY0381 *

Hs00612265 ml ZCCHC6 containing 6 GGAAGCAGGAAGTC CTG AAAAC AAG chromosome 4 open reading

ASSAY0387

Hs00260452 ml C4orf14 frame 14 GTTACTCCAGATTCCAATGGGTGGA

ASSAY0393 Hs00295454 s1 N/A N/A AGCTAAGAGGTTTCCAGTGCAATAC

ASSAY0394* Hs00325999 ml TET2 tet oncogene family member 2 GGCAGCACATTGGTATGCACTCTCA

ASSAY0400 Hs00379387 ml RAD54L2 RAD54-like 2 (S. cerevisiae) GGCTGCCTCAGGTTCCCAGGGACCT

LSM14A, SCD6 homolog A (S.

ASSAY0401

Hs00385941 ml LSM14A cerevisiae) GCCCTTGCCAAAGTTCGATCCTTTG

TRAF2 and NCK interacting

ASSAY0402*

Hs00390635 ml TNIK kinase ACCCATCAGAGCAAGCAACCCTGAT

ASSAY0407 Hs00540709 s1 TMEM203 transmembrane protein 203 CGGGAGCTGGTGCAGTGGCTAGGCT

ASSAY0415 Hs00608266 ml BYSL bystin-like ACCCTCCTGCCAGGCGCACCCTGGC

ASSAY0421 * Hs00609836 ml AARS alanyl-tRNA synthetase CAAAATTTGGGGCTGGATGACACCA ASSAY0423* Hs00610216 ml SH2D2A SH2 domain protein 2A GGGCTACACTGCGGCATCTCCCCAG

PWP2 periodic tryptophan

ASSAY0425*

Hs00610478 ml PWP2 protein homolog (yeast) GGCTGGCCAAGTACTTCTTCAATAA

BUD31 homolog (S.

ASSAY0432*

Hs00696974 ml BUD31 cerevisiae) GAAAGCCATCAGCAGAGAACTCTAT

ASSAY0433 Hs00697331 ml YTHDF1 YTH domain family, member 1 TGGTGCGCAAGGAACGGCAGAGTCG zinc finger, MYND-type

ASSAY0434

Hs00698392 ml ZMYND17 containing 17 GTGGCGGCATTCCATCCAGG I I I I C nuclear factor, interleukin 3

ASSAY0437*

Hs00705412 s1 NFIL3 regulated ACTCTCCACAAAGCTCGCTGTCCGA chromosome 18 open reading

ASSAY0450

Hs00743508 s1 C18orf32 frame 32 AGGTAGAA I I I I G G G AG G T AATAAT

ASSAY0463 Hs00762481 s1 RPL36 ribosomal protein L36 CCTTCTCCCCGTCGCTGTCCGCAGC

SAP domain containing

ASSAY0465

Hs00793492 ml SARNP ribonucleoprotein ACTGTTGATGTGGCAGCAGAGAAGA brain abundant, membrane

ASSAY0473*

Hs00234720 g1 BASP1 attached signal protein 1 CCCAGAGCCGAACTCCAAGATGGGA tyrosine 3- monooxygenase/tryptophan 5-

ASSAY0478*

monooxygenase activation

Hs00237047 ml YWHAZ protein, zeta polypeptide GATAAAAAGAACATCCAGTCATGGA cell division cycle 25 homolog

ASSAY0484

Hs00244740 ml CDC25B B (S. pombe) GGCGGAGCAGACGTTTGAACAGGCC

ASSAY0485* Hs00247369 ml USP21 ubiquitin specific peptidase 21 TCTGATGACAAGATGGCTCATCACA

ASSAY0489 Hs00248408 ml Sep-06 septin 6 AGAAAGAGCTGCACGAGAAGTTTGA

ASSAY0494* Hs00252433 ml CDC42SE1 CDC42 small effector 1 AGAGCAGGGTTCCGAGTCTGAGGAA

FXYD domain containing ion

ASSAY0495

Hs00253715 ml FXYD2 transport regulator 2 GTGGTACCTGGGCGGCAGCCCCAAG

N(alpha)-acetyltransferase 35,

ASSAY0497

Hs00254277 ml NAA35 NatC auxiliary subunit ACTCACTGTGTTCGGCCATTCTGTA

RNA binding motif protein

ASSAY0499 RBM8A;GNRH 8A;gonadotropin-releasing

Hs00254802 s1 R2 hormone (type 2) receptor 2 CCCTTCCTTGTCTGGGGCCTGGACA coenzyme Q10 homolog B (S.

ASSAY0504*

Hs00257861 ml COQ10B cerevisiae) CGCCCGTGCGGAATGGCAGATATTT

ASSAY0509* Hs00260517 s1 CAPNS2 calpain, small subunit 2 G ATCG AG GTCTTGG AG AAG CTCTTG

GINS complex subunit 4 (Sld5

ASSAY0510

Hs00260545 ml GINS4 homolog) TTGGAGCAGGCCTGGATGAATGAAA chromosome 5 open reading

ASSAY0513*

Hs00260900 ml C5orf32 frame 32 CAGGAGCCTCCTAAAACCACAGTGT pyridine nucleotide-disulphide

ASSAY0517*

Hs00261978 ml PYROXD2 oxidoreductase domain 2 TGGTGGCTGCAGCGTACCTGCAGAG

ASSAY0518 Hs00262488 ml FIZ1 FLT3-interacting zinc finger 1 TGCACCACCAGGTCGTCCACACTGG asparagine-linked

glycosylation 2, alpha-1 ,3-

ASSAY0521

mannosyltransferase homolog

Hs00263798 ml ALG2 (S. cerevisiae) TAGTGTGCGACCAGGTGTCTGCCTG

SWI/SNF related, matrix

associated, actin dependent

ASSAY0534

regulator of chromatin,

Hs00268265 ml SMARCC1 subfamily c, member 1 CCAAACTCCCTGCAAAGTGTTTCAT phosphoribosylaminoimidazole

carboxylase,

ASSAY0545 phosphoribosylaminoimidazole

succinocarboxamide

Hs00272390 ml PAICS synthetase ATGGCGACAGCTGAGGTACTGAACA beta-site APP-cleaving

ASSAY0548

Hs00273238 ml BACE2 enzyme 2 ACACTTGCCAAGCCATCAAGTTCTC N-acetyltransferase 6 (GCN5-

ASSAY0549

Hs00273329 s1 NAT6 related) CCGCACCTCCCGCCTGCACTCCCTG glycogen synthase kinase 3

ASSAY0553*

Hs00275656 ml GSK3B beta AGAAATAATCAAGGTCCTGGGAACT

ASSAY0559* Hs00291515 ml IKBIP IKBKB interacting protein TAATTTCAGAAAAGCTTGAGTCTAC hypothetical protein

ASSAY0561 *

Hs00292281 ml LOC439949 LOC439949 AAGCTGCAAAGGTTCTGCCCTGATG

ASSAY0566 Hs00293370 ml SPPL3 signal peptide peptidase 3 TATTTAAAGGGCGACCTCCGGCGGA

BTB (POZ) domain containing

ASSAY0567

Hs00298028 s1 BTBD9 9 CCACCACTGGTCACGGTGCTCCCTG solute carrier family 38,

ASSAY0568*

Hs00298999 ml SLC38A10 member 10 TTCGCCTGCCAGTCCCAGGTGCTGC proline, glutamate and leucine

ASSAY0572*

Hs00300396 ml PELP1 rich protein 1 TCTCTCAAAGGCAAGCTGGCCTCAT

RAP1 GTPase activating

ASSAY0573

Hs00324432 ml RAP1 GAP2 protein 2 TTTCAAAGGTTTCCGAGGAGGCCTG nuclear fragile X mental

ASSAY0574* retardation protein interacting

Hs00325168 ml NUFIP2 protein 2 AAGAAAACAGGCTATGGTGAACTAA

ASSAY0575* Hs00325918 ml ALPK1 alpha-kinase 1 TTCTGGGGAGGTATGTTGGGAAAGA

HECT, UBA and WWE domain

ASSAY0577*

Hs00328354 ml HUWE1 containing 1 G AAAAAG ATC AG ATG G G G A AC AG G A chromosome 20 open reading

ASSAY0578

Hs00329245 s1 C20orf1 17 frame 1 17 GAGGACATGATGCTGGGCCCAAGTC phosphoenolpyruvate

ASSAY0583 carboxykinase 2

Hs00356436 ml PCK2 (mitochondrial) CCCTGGCCTGCGGCTTAACTGGCAT cannabinoid receptor 2

ASSAY0591

Hs00361490 ml CNR2 (macrophage) ACAACACAACCCAAAGCCTTCTAGA

SGT1 , suppressor of G2 allele

ASSAY0593

Hs00362511 g1 SUGT1 of SKP1 (S. cerevisiae) CTGCAACATCCCAGAGGTTTTTCCA

ASSAY0596 Hs00364293 ml CDK1 cyclin-dependent kinase 1 TTGGATTTGCTCTCGAAAATGTTAA

RAB24, member RAS

ASSAY0599

Hs00365678 g1 RAB24 oncogene family GTATTTGGGACACAGCAGGCTCTGA serpin peptidase inhibitor,

ASSAY0601 clade B (ovalbumin), member

Hs00366434 ml SERPINB6 6 AGATGGCCCAGATACTTTCTTTCAA

XK, Kell blood group complex

ASSAY0613 subunit-related family, member

Hs00372436 s1 XKR8 8 AGCTCCGAGTGGCTGTACCGGGTGA

GRB2-associated binding

ASSAY0614*

Hs00373045 ml GAB2 protein 2 GAGAGCACAGACTCCCTGAGAAATG breast carcinoma amplified

ASSAY0616

Hs00375126 ml BCAS3 sequence 3 GTCACCCTTGCATGGGAAACTGAAC amyloid beta (A4) precursor

ASSAY0624 protein-binding, family B,

Hs00377427 ml APBB1 member 1 (Fe65) TCCCCAG AG G ACACAG ATTCCTTCT ubiquitin protein ligase E3

ASSAY0625

Hs00378208 ml UBR4 component n-recognin 4 CACTTGCTTGGCAAGACACAACACT ubiquitin protein ligase E3

ASSAY0626

Hs00378210 ml UBR4 component n-recognin 4 TGGAGCCACCAGGCTGACAGATAAG

ASSAY0629 Hs00378902 ml ZNF337 zinc finger protein 337 CAGGCCCCTGTGCAGGAATATATGC

GrpE-like 1 , mitochondrial (E.

ASSAY0633

Hs00379355 ml GRPEL1 coli) CGTTGTCTCTCAGGCCATCTCCCCG complement component 5a

ASSAY0637

Hs00383718 ml C5AR1 receptor 1 AGACCAGAACATGAACTCCTTCAAT prolyl-tRNA synthetase 2,

ASSAY0638

Hs00384448 ml PARS2 mitochondrial (putative) GGCTGGGATTGCGGTGCCTGTGCTT

ASSAY0640 Hs00385075 ml MAPK3 mitogen-activated protein AGATGTCTACATTGTGCAGGACCTG kinase 3

chromosome 4 open reading

ASSAY0644*

Hs00386171 ml C4orf3 frame 3 TATTTTTTGCCATGACTTGTTCGCT mitogen-activated protein

ASSAY0645*

Hs00387426 ml MAP2K4 kinase kinase 4 CAAATAATGGCAGTTAAAAGAATTC

SEC16 homolog A (S.

ASSAY0648*

Hs00389570 ml SEC16A cerevisiae) AACCTAAGAAGGGTGAATCCTGGTT

ASSAY0649 Hs00390028 ml TCF20 transcription factor 20 (AR1 ) GGAAATAGCCAGAGAGATGAAATGT

ASSAY0650 Hs00390576 ml ZNF862 zinc finger protein 862 GCTGTTGGCATCCTTGGGACCTGCT

Smg-6 homolog, nonsense

ASSAY0651 mediated mRNA decay factor

Hs00391737 ml SMG6 (C. elegans) ACGCAAGACAGTAAAATATGCCTTG

ASSAY0655* Hs00394683 ml LST1 leukocyte specific transcript 1 AGGCCACAAGCTCTGGATGAGGAAC

ASSAY0656 Hs00395045 ml STMN3 stathmin-like 3 CCAGTACGGGGACATGGAGGTGAAG

ASSAY0660* Hs00402617 ml MPZL3 myelin protein zero-like 3 GTGCCTGGATTCAGACTATGAAGAG

ASSAY0661 * Hs00405469 ml JMJD1 C jumonji domain containing 1 C TCAAAAGCAGGAATTCTCAAGAAAT

ASSAY0668* Hs0041 1 197 ml LRRK2 leucine-rich repeat kinase 2 GACAAGAACAAGCCAACTG I I I I CT

ASSAY0684* Hs00417273 ml LRRK2 leucine-rich repeat kinase 2 TTTGGCCCTCCTCACTGAGACTATT structural maintenance of

ASSAY0686* chromosomes flexible hinge

Hs00418955 ml SMCHD1 domain containing 1 AAGGA I I I I AAATGGACAGGAACAG

N-ethylmaleimide-sensitive

ASSAY0687

Hs00419531 ml NSF factor TTTCCAGTCTGGCCAGCATGTGATT tumor necrosis factor receptor

superfamily, member 10c,

ASSAY0695*

decoy without an intracellular

Hs00427795 g1 TNFRSF10C domain CGGAAGTGTAGCAGGTGCCCTAGTG shisa homolog 5 (Xenopus

ASSAY0702

Hs00429977 ml SHISA5 laevis) CCGGGTGCACGTGGTGAGGTGTGTA tumor necrosis factor, alpha-

ASSAY0712*

Hs00537038 ml TNFAIP8L1 induced protein 8-like 1 TGCTTCGAGAGTAGGCCATGGACAC chromosome 5 open reading

ASSAY0713

Hs00538077 ml C5orf41 frame 41 ACACCCACAGACAGCATCGCACAGA chromosome 19 open reading

ASSAY0722

Hs00541991 ml C19orf46 frame 46 CTCCGGAAGCCTCAGGACAAGAAGA chromosome 22 open reading

ASSAY0725*

Hs00543135 ml C22orf30 frame 30 CACAAGCAGCCACACCATGTTACCA leucine carboxyl

ASSAY0727

Hs00544314 s1 LCMT2 methyltransferase 2 CGGAGCCGTGAGCGTCGGGCAGGCG hematological and neurological

ASSAY0734*

Hs00602957 ml HN1 expressed 1 CCAAGTCAGCAGGTGCCAAGTCTAG

SEC1 1 homolog A (S.

ASSAY0744

Hs00819308 ml SEC1 1A cerevisiae) CTATCCTAAATTTAAGTATGCAGTT

Sfi1 homolog, spindle

ASSAY0745

Hs00826823 ml SFI1 assembly associated (yeast) GCAGAACCTCTGGTCCTGTCGGCGG

ASSAY0748 Hs00830558 g1 FOXN3 forkhead box N3 TCTAGGGACTTGGTGTTGCTTGGAA deleted in lymphocytic

ASSAY0754* leukemia 2 (non-protein

Hs00867656 s1 DLEU2 coding) AAAAATTTA I I I I ACACATGTCAAG transformer 2 beta homolog

ASSAY0763*

Hs00907493 ml TRA2B (Drosophila) ATCAGATTTATAGAAGGCGGTCACC

ASSAY0778 Hs00939205 ml RNF24 ring finger protein 24 GCCTTCCACAGAAAGTGCCTTATTA

ASSAY0781 * Hs00943178 g1 PGK1 phosphoglycerate kinase 1 AGCCCACAGCTCCATGGTAGGAGTC

ST6 beta-galactosamide

ASSAY0784

Hs00949382 ml ST6GAL1 alpha-2,6-sialyltranferase 1 CCAAAGTGGTACCAGAATCCGGATT ASSAY0795* Hs00971411 ml ANXA3 annexin A3 TTACTGTTGGCCATAGTTAATTGTG

Bruton agammaglobulinemia

ASSAY0797

Hs00975865 ml BTK tyrosine kinase TTATCCCTTCCAG GTTGTATATG AT

ASSAY0806 Hs00997789 ml PSEN1 presenilin 1 TTC ATTTACTTG GGGGAAGTGTTTA

ASSAY0818 Hs01018736 g1 UBL3 ubiquitin-like 3 GCCAAACTCTCAAGGTCAGAGGAAT actin related protein 2/3

ASSAY0820

Hs01031740 ml ARPC2 complex, subunit 2, 34kDa TGAAAACAATCACGGGGAAGACGTT

ST6 (alpha-N-acetyl- neuraminyl-2,3-beta-

ASSAY0821 * galactosyl-1 ,3)-N- acetylgalactosaminide alpha-

Hs01032565 ml ST6GALNAC2 2,6-sialyltransferase 2 CCTGTGACCAGGTCAGTGCCTATGG

ASSAY0822 Hs01032700 ml LBR lamin B receptor TTATTGTTCTGAAACTTTGTGGTTA thioredoxin-related

ASSAY0842

Hs01062739 ml TMX4 transmembrane protein 4 TCTGAGCGTTCTGAGCAGAATCGGA

ASSAY0843* Hs01064052 g1 SEPX1 selenoprotein X, 1 TTGTCCCTAAAGGCAAAGAAACTTC tetratricopeptide repeat and

ASSAY0844

Hs01064792 ml TRANK1 ankyrin repeat containing 1 TAAAG AAGG AAG GTATTGTTCAG G A v-ral simian leukemia viral

ASSAY0862* oncogene homolog B (ras

Hs01095303 ml RALB related; GTP binding protein) AACGTGGACAAGGTGTTCTTTGACC

ASSAY0866* Hs01 108442 s1 N/A N/A CCCTAACATTTCAAGAAGAAGCAGA beta-site APP-cleaving

ASSAY0874*

HsO 1 123242 ml BACE1 enzyme 1 GAGATTGCCAGGCCTGACGACTCCC zinc finger, DHHC-type

ASSAY0876

Hs01372307 ml ZDHHC18 containing 18 ACCTCCCAGCCTAATTGACCGGAGG myxovirus (influenza virus)

ASSAY0882*

Hs01550808 ml MX2 resistance 2 (mouse) GAATGCCTACTTCTTGGAAACCAGC

ASSAY0885 Hs01555410 ml IL1 B interleukin 1 , beta CAGATGAAGTGCTCCTTCCAGGACC

ASSAY0886* Hs01564142 ml GLIPR1 GLI pathogenesis-related 1 CT AT AC ATG ACTTG G G ACC C AG C AC influenza virus NS1 A binding

ASSAY0887*

Hs01573482 ml IVNS1ABP protein GAGTGGCTGTTCTTAATGGAAAACT

ASSAY0895 Hs01593434 s1 N/A N/A GCTCCAGAGCTTACTGACATGGGCC coiled-coil domain containing

ASSAY0899*

Hs01632947 g1 CCDC72 72 GGAATTAAGTGTTGTCTTGGAGCTG

ASSAY0912* Hs01932078 s1 COMMD6 COMM domain containing 6 AGATTAAGATTGACCATTGCTCCTT dihydropyrimidine

ASSAY0919

Hs02510591 s1 DPYD dehydrogenase GATGGGTGTACAAACTCATCCTCTT

MT- mitochondrially encoded

ASSAY0921 ND4L;CCDC1 NADH 4L;coiled-coil domain

Hs02596877 g1 04 containing 104 CCCTCAACACCCACTCCCTCTTAGC guanine nucleotide binding

ASSAY0922 GNG10;LOC6 protein (G protein), gamma

Hs02597217 g1 53503 10;GNG10 pseudogene GAGAGGATCAAGGTCTCTCAGGCAG

NLR family, apoptosis

ASSAY0927

Hs03037952 ml NAIP inhibitory protein GCGTGGTGGAAATTGCCAAAGTAGC

ASSAY0935* Hs00991010 ml IL1 R1 interleukin 1 receptor, type I TATTACAGTGTGGAAAATCCTGCAA

ASSAY0941 * Hs00328784 s1 MTMR3 myotubularin related protein 3 CCCTCGGGAAGGTTGGTATTGAGGG

ASSAY0947* Hs00254569 s1 HRH2 histamine receptor H2 GGTCACCCCAGTTCGGGTCGCCATC

NLR family, pyrin domain

ASSAY0957

Hs00536435 ml NLRP12 containing 12 ACTACGGACTTTGTGGCTGAAGATC chromosome 1 open reading

ASSAY0960*

Hs00984297 ml C1 orf175 frame 175 AATGAAGTGAAAGCTGCTCTGGATA dehydrogenase/reductase

ASSAY0962*

Hs0021 1306 ml DHRS7 (SDR family) member 7 CTTTAAGAGTGGTGTGGATGCAGAC HECT, UBA and WWE domain

ASSAY0969*

Hs00948075 ml HUWE1 containing 1 TCAATTGGCCAAGGTATTTCCCAGC

ASSAY0971 * Hs00391048 ml MEGF9 multiple EGF-like-domains 9 GTGCAACAGTTCTGGGAAATGCCAG

T-cell, immune regulator 1 ,

ASSAY0986 ATPase, H+ transporting,

Hs00990751 ml TCIRG1 lysosomal V0 subunit A3 ACCCCGCTCCCTACACCATCATCAC misshapen-like kinase 1

ASSAY0987

Hs00179553 ml MINK1 (zebrafish) ACAGGTGTACAAGGGTCGGCATGTC

Parkinson disease 7 domain

ASSAY0997

Hs00699585 ml PDDC1 containing 1 TCCACTCTGAGAGCAAACCCATCTG inhibitor of growth family,

ASSAY1002

Hs00219444 ml ING3 member 3 GGTGCAGAATGCAATGGATCAACTA low density lipoprotein

AS SAY 1004 receptor-related protein 8,

Hs00182998 ml LRP8 apolipoprotein e receptor GGACGACTGCCCCAAGAAGACCTGT poly (ADP-ribose) polymerase

ASSAY1007*

Hs00226343 ml PARP8 family, member 8 CAACTGGAGCTCAGGTGGTAGATCT actin related protein 2/3

ASSAY1019*

Hs00271722 ml ARPC5 complex, subunit 5, 16kDa GTCAGGCAGTGAAGGACCGGGCAGG spectrin, beta, non-erythrocytic

ASSAY1026

Hs00162271 ml SPTBN1 1 GCTCTGGGCACACAGGTGAGGCAGC

ASSAY1037 Hs00300550 ml LAMA1 laminin, alpha 1 GGCAGAGAGGCCTGTTTCCTGCCAT

TAF6 RNA polymerase II,

TATA box binding protein

ASSAY1039*

(TBP)-associated factor,

Hs00425763 ml TAF6 80kDa GAGCCTCCTGCTGAAACACTGTGCT

ASSAY1042 Hs00202482 ml ACOT9 acyl-CoA thioesterase 9 CTGAAAATAAAGGGCCGGCATTTGT major histocompatibility

ASSAY1051

Hs03045171 ml HLA-E complex, class I, E CTGCTTCACCTGGAGCCCCCAAAGA

ASSAY1058* Hs00369593 ml RBM33 RNA binding motif protein 33 GAAAATTTCAGTTCTCAGGGTGTTA sorbin and SH3 domain

ASSAY1059*

Hs00195059 ml SORBS3 containing 3 ATGGCTGGTTTGTGGGTGTCTCCCG

ASSAY"! 061 * Hs00330542 ml TPCN1 two pore segment channel 1 TACCTCCAGGAAGGCGAGAACAACG

YKT6 v-SNARE homolog (S.

ASSAY1064

Hs00559914 ml YKT6 cerevisiae) TATAAAACTGCCCGGAAACAAAACT

HECT, UBA and WWE domain

ASSAY"! 078*

Hs00229975 ml HUWE1 containing 1 TGAGAATGACAGGAGCCATCCGCAA ubiquitin protein ligase E3

AS SAY 1084

Hs00390223 ml UBR4 component n-recognin 4 ACATGACCACAGGTACAGAATCAGA zinc finger, CCHC domain

ASSAY"! 093*

Hs00226352 ml ZCCHC6 containing 6 AAAGGCTCTTCAGGTAGCCTTTCCA complement component 5a

ASSAY1097

Hs00704884 s1 C5AR1 receptor 1 TATTTA I I I I ATGGCAAGTTGGAAA sortilin-related receptor, L(DLR

ASSAY1 103

Hs00300475 s1 SORL1 class) A repeats-containing CAGAAGACACACAGCTGCCTGTTCT _ 1 τ,α _

Table 10: Informative probes for Retrospective Intraperson Progression or Non-

Progression (AD) (All probes have p-value <0.5)

Sequence No.

(DiaGenic Context Sequence (Oligonucleotide Probe ID) Assay ID Gene Symbol Gene name sequence)

membrane metallo-

ASSAY0002 HsOO-153510 ml MME endopeptidase TGAAGAAAAGGCCTTAGCAATTAAA solute carrier family 12

(potassium/chloride

ASSAY0006 Hs00220373 ml SLC12A9 transporters), member 9 CTCCGGCCTCGGTGGCATGAAGCCC

Rho GTPase activating

ASSAY0007 Hs00221912 ml ARHGAP22 protein 22 AGTGTGAAAAGAATCGAAGAAGGGA ubiquitin-conjugating

enzyme E2B (RAD6

ASSAY0013 Hs00163311 ml UBE2B homolog) CACCTTTTGAAGATGGTACTTTTAA killer cell lectin-like receptor

ASSAY0015 HsOO 174469 ml KLRB1 subfamily B, member 1 TTCCTCGGGATGTCTGTCAGGGTTC abhydrolase domain

ASSAY0053 Hs00221 104 ml ABHD6 containing 6 CGTGTGTCCTGCTGGCCTGCAGTAC lysophosphatidylcholine

ASSAY0077 Hs00227357 ml LPCAT1 acyltransferase 1 GAAGATCACATTCGCTGACTTCCAC elongation factor RNA

ASSAY0081 Hs00228559 ml ELL3 polymerase ll-like 3 CAGAATACAAGGTCCTGGAAGACAA membrane metallo-

ASSAY0098 Hs00153519 ml MME endopeptidase TCCAGGCAATTTCAGGATTATTGGG low density lipoprotein

receptor-related protein

ASSAY01 18 Hs00158875 ml LRPAP1 associated protein 1 AAGGCCCAGCGACTGCATCTTCCTC

ASSAY01 19 Hs00159537 ml NBN nibrin CCCGGCAGGAGGAGAACCATACAGA superoxide dismutase 2,

ASSAY0133 Hs00167309 ml SOD2 mitochondrial GGAACAACAGGCCTTATTCCACTGC

ASSAY0162 Hs00177028 ml PKN1 protein kinase N1 TGGCAGCACCAAGGACCGGAAGCTG

NEDD8 activating enzyme

ASSAY0172 Hs00182671 ml NAE1 E1 subunit 1 GACCGGCAGCTGAGGTTGTGGGGTG

ASSAY0186 Hs00189566 ml GOLGB1 golgin B1 CAGCAACTGAACAGCAACTTCTCTC

ASSAY0223 Hs00215938 ml RNF31 ring finger protein 31 TGCCCCACAACCGGATGCAGGCCCT lysine (K)-specific

ASSAY0225 Hs00218331 ml KDM3A demethylase 3A TTCTT AAAAAG G TATC AG A AG AG C A

ASSAY0242 Hs00276830 ml RUNDC2A RUN domain containing 2A CAGTGAAACAGTGCCAGATCCGCTT tetratricopeptide repeat

ASSAY0245 Hs00326671 ml TTC14 domain 14 AGAGAGAGGAGGACAGTTAGAAGAA

ASSAY0254 Hs00382453 ml XP05 exportin 5 TTGCGCTTATAAGAACCCACAATAC

Taxi (human T-cell

leukemia virus type I)

ASSAY0292 Hs00195718 ml TAX1 BP1 binding protein 1 AAACAACTCTTGCAGGATGAGAAAG polymerase (RNA) III (DNA

directed) polypeptide C

ASSAY0299 Hs00197744 ml POLR3C (62kD) CAGATAACAAGGAGCCCATTCCAGA

ASSAY0334 Hs00206922 ml CP1 10 CP1 10 protein TCTCCACTG CTTAACATTG AG AAAA

NEDD4 binding protein 2-

ASSAY0337 Hs00208459 ml N4BP2L2 like 2 ATTGTCTCGAATTCTGCTTGGTCAG family with sequence

ASSAY0344 Hs0021 1234 ml FAM164A similarity 164, member A ACATAGCCAGGCCAGATGGGGACTG _ 1 ¾ 1 _

ASSAY0359 Hs00214745 ml DPP8 dipeptidyl-peptidase 8 CTGCCTGCTCCAAGTGATTTCAAGT

BTB (POZ) domain

ASSAY0361 Hs00215064 ml BTBD2 containing 2 TCGCTGCAGGTCCCGCACAGTCGGG chromosome 19 open

ASSAY0366 Hs00215835 ml C19orf60 reading frame 60 CAGCAGCTGAAAATGAAGGTAATTA zinc finger protein 64

ASSAY0369 Hs00217022 ml ZFP64 homolog (mouse) AGACAATCACAGTTTCAGCTCCAGA

FK506 binding protein 2,

ASSAY0376 Hs00234404 ml FKBP2 13kDa CACTACACGGGGAAGCTGGAAGATG zinc finger, CCHC domain

ASSAY0381 Hs00612265 ml ZCCHC6 containing 6 GGAAGCAGGAAGTCCTGAAAACAAG

LSM14A, SCD6 homolog A

ASSAY0401 Hs00385941 ml LSM14A (S. cerevisiae) GCCCTTGCCAAAGTTCGATCCTTTG

ASSAY0421 Hs00609836 ml AARS alanyl-tRNA synthetase CAAAATTTGGGGCTGGATGACACCA

ASSAY0423 Hs00610216 ml SH2D2A SH2 domain protein 2A GGGCTACACTGCGGCATCTCCCCAG

PWP2 periodic tryptophan

AS3AY0425 Hs00610478 ml PWP2 protein homolog (yeast) GGCTGGCCAAGTACTTCTTCAATAA mitochondrial ribosomal

ASSAY0429 Hs0061 1 133 ml MRPL10 protein L10 CGCTGCTAGGTGGCTGCATTGATGA nuclear factor, interleukin 3

ASSAY0437 Hs00705412 s1 NFIL3 regulated ACTCTCCACAAAGCTCGCTGTCCGA

ASSAY0452 Hs00747351 mH CLTA clathrin, light chain (Lea) GGGGTCCGGATGCTGTTGATGGAGT

ASSAY0463 Hs00762481 s1 RPL36 ribosomal protein L36 CCTTCTCCCCGTCGCTGTCCGCAGC

SAP domain containing

ASSAY0465 Hs00793492 ml SARNP ribonucleoprotein ACTGTTGATGTGGCAGCAGAGAAGA asparagine-linked

glycosylation 2, alpha-1 ,3- mannosyltransferase

ASSAY0521 Hs00263798 ml ALG2 homolog (S. cerevisiae) TAGTGTGCGACCAGGTGTCTGCCTG

ASSAY0524 Hs00264721 ml MSH6 mutS homolog 6 (E. coli) TGCCCCCACCAGTTGTGACTTCTCA melanocortin 1 receptor

(alpha melanocyte

stimulating hormone

ASSAY0532 Hs00267168 s1 MC1 R receptor) GCAGGACGCTCAAGGAGGTGCTGAC

SWI/SNF related, matrix

associated, actin

dependent regulator of

chromatin, subfamily c,

ASSAY0534 Hs00268265 ml SMARCC1 member 1 CCAAACTCCCTGCAAAGTGTTTCAT zinc finger protein 36, C3H

ASSAY0546 Hs00272828 ml ZFP36L2 type-like 2 GTCGACTTCTTGTGCAAGACAGAGA

SGT1 , suppressor of G2

allele of SKP1 (S.

ASSAY0593 Hs00362511 g1 SUGT1 cerevisiae) CTGCAACATCCCAGAGGTTTTTCCA ubiquitin protein ligase E3

ASSAY0625 Hs00378208 ml UBR4 component n-recognin 4 CACTTGCTTGG C AAG AC AC AAC ACT chromosome 1 open

ASSAY0632 Hs00379295 ml C1 orf144 reading frame 144 AACCCATCCTCGACAGGCCAACCAG jumonji domain containing

ASSAY0661 Hs00405469 ml JMJD1 C 1 C TCAAAAGCAGGAATTCTCAAGAAAT mitogen-activated protein

ASSAY0666 Hs00406365 ml MAPKBP1 kinase binding protein 1 AGAGGACCTCAGCTCCAAGGTGACC glioma tumor suppressor

ASSAY0674 Hs00414236 ml GLTSCR2 candidate region gene 2 CGCACGAGCGGTGGCTTGTTGTCAG _ 11 _

ASSAY0679 Hs00415699 ml LOC149837 hypothetical LOC149837 TCACCACCTGCCGGCAATCAGCCAT small nucleolar RNA host

ASSAY0683 Hs00417251 ml SNHG6 gene 6 (non-protein coding) TAGCTGGGCTCTGCGAGGTGCAAGA

ASSAY0684 Hs00417273 ml LRRK2 leucine-rich repeat kinase 2 TTTGGCCCTCCTCACTGAGACTATT structural maintenance of

chromosomes flexible

ASSAY0686 Hs00418955 ml SMCHD1 hinge domain containing 1 AAGGA I I I I AAATGGACAGGAACAG hypothetical protein

ASSAY0689 Hs00419820 g1 LOC728975 LOC728975 CTGCGTGACCTTGGGCTCTCAGCCC deltex homolog 2

ASSAY0718 Hs00539707 ml DTX2 (Drosophila) GGCCGCAAGGTCCTAGAGCTCCTGA dynein, light chain, LC8-

ASSAY0719 Hs00540753 ml DYNLL2 type 2 GCCTCCGTGAAGTGTCACACCATGT

ASSAY0726 Hs00543883 s1 HIST1 H4C histone cluster 1 , H4c TATGGCTTCGGCGGCTGAATCTAAG mitochondrial ribosomal

ASSAY0740 Hs00606809 g1 MRPL41 protein L41 TCCGGTCCAGGGCGCGGCATGGGCG tumor necrosis factor

receptor superfamily,

ASSAY0741 Hs00606874 g1 TNFRSF13C member 13C CGGAGACAAGGACGCCCCAGAGCCC deleted in lymphocytic

leukemia 2 (non-protein

ASSAY0754 Hs00867656 s1 DLEU2 coding) AAAAATTTA I I I I ACACATGTCAAG

ASSAY0756 Hs00894392 ml TBX21 T-box 21 ACAATGTGACCCAGATGATTGTGCT

ASSAY0786 Hs00953178 ml EPHA4 EPH receptor A4 CGACCCCAGATCTGCAAGGGAGTAG

ASSAY0795 Hs00971411 ml ANXA3 annexin A3 TTACTGTTGGCCATAGTTAATTGTG

ASSAY0799 Hs00982887 g1 BCL2L12 BCL2-like 12 (proline rich) CCGCCCAGCCCAGAATTACAGGGTC beta-site APP-cleaving

ASSAY0874 HsO 1 123242 ml BACE1 enzyme 1 GAGATTGCCAGGCCTGACGACTCCC

COMM domain containing

ASSAY0912 Hs01932078 s1 COMMD6 6 AGATTAAGATTGACCATTGCTCCTT

ASSAY0935 Hs00991010 ml IL1 R1 interleukin 1 receptor, type I TATTACAGTGTGGAAAATCCTGCAA chromosome 1 open

ASSAY0960 Hs00984297 ml C1 orf175 reading frame 175 AATGAAGTGAAAGCTGCTCTGGATA dehydrogenase/reductase

ASSAY0962 Hs0021 1306 ml DHRS7 (SDR family) member 7 CTTTAAGAGTGGTGTGGATGCAGAC hypothetical protein

ASSAY0992 Hs00293951 ml LOC375295 LOC375295 CCCCGCTCAGTTCAATATTTCAAGT family with sequence

ASS AY 1000 Hs00403541 ml FAM129C similarity 129, member C CTGCCCTGAATCCTTGGGAGACCAT

TAF6 RNA polymerase II,

TATA box binding protein

(TBP)-associated factor,

ASSAY^"! 039 Hs00425763 ml TAF6 80kDa GAGCCTCCTGCTGAAACACTGTGCT slowmo homolog 1

ASSAY1047 Hs00398895 ml SLM01 (Drosophila) CAATGCAAAGAAGGGGTGGGCTGCT

ASSAY1077 Hs01547450 ml FIP1 L1 FIP1 like 1 (S. cerevisiae) TAGAAAGTGGACATTCCTCTGGTTA

ASSAY1081 Hs00365632 ml DGUOK deoxyguanosine kinase AGGCTTCTCCCCAGGTTTGTTTGAA zinc finger, CCHC domain

ASSAY1093 Hs00226352 ml ZCCHC6 containing 6 AAAGGCTCTTCAGGTAGCCTTTCCA Table 11 : Informative probes for Retrospective modelling Interperson L1 versus L2

(AD) (All probes have p-value

Sequence No.

(DiaGenic Gene Context Sequence (Oligonucleotide Probe ID) Assay ID Symbol Gene name sequence)

ASSAY0024 splicing factor,

HsOO-191 108 ml SFRS1 1 arginine/serine-rich 1 1 CCGCCGGATGATTCGCCTTTGCCAG

ASSAY0037 cullin-associated and

Hs00218384 ml CAND1 neddylation-dissociated 1 GTACAACTAAGGTAAAGGCAAACTC

ASSAY0038 Hs00218782 ml RNF1 14 ring finger protein 1 14 TGCCCTGCGGACACGTC I I I I GCTC cytidine monophosphate N-

ASSAY0039 acetyl neuraminic acid

Hs00218814 ml CMAS synthetase TCAGAAAGGAGTTCGTGAAGTGACC solute carrier family 44,

ASSAY0052

Hs00220814 ml SLC44A2 member 2 AAACGAGAACAAACCCTATCTGTTT

ASSAY0066 Hs00224697 ml CASD1 CAS1 domain containing 1 TTTGGCATATTCTCAGGGTGCATTT

Notch homolog 2

ASSAY0070

Hs00225747 ml NOTCH2 (Drosophila) GTGCCTTTACTGGCCGGCACTGTGA

ASSAY0077 lysophosphatidylcholine

Hs00227357 ml LPCAT1 acyltransferase 1 GAAGATCACATTCGCTGACTTCCAC membrane metallo-

ASSAY0098

Hs00153519 ml MME endopeptidase TCCAGGCAATTTCAGGATTATTGGG

ADAM metallopeptidase

ASSAY0099

Hs00153853 ml ADAM 10 domain 10 AAACAGTGCAGTCCAAGTCAAGGTC

ASSAY0104 Hs00154683 ml DARS aspartyl-tRNA synthetase GTGGAGGCATTGGATTGGAACGAGT

ASSAY0126 Hs00162077 ml SOAT1 sterol O-acyltransferase 1 CCATCTTGCCAGGTGTGCTGATTCT

ASSAY0140 Hs00173196 ml ZNF146 zinc finger protein 146 AGGATCTGCGCGGAAGAAGCCTGAG

ASSAY0159 protein kinase, cAMP-

HsOO 176944 ml PRKACB dependent, catalytic, beta GAGAATCCAACTCAGAATAATGCCG

ASSAY0162 Hs00177028 ml PKN1 protein kinase N1 TGGCAGCACCAAGGACCGGAAGCTG

ASSAY0164 ADAM metallopeptidase

Hs00177638 ml ADAM9 domain 9 (meltrin gamma) TGCCACTGGGAATGCTTTGTGTGGA

ASSAY0165 Hs00177790 ml STK17B serine/threonine kinase 17b TGATATTGGAATATGCTGCAGGTGG

ASSAY0174 Hs00183425 ml SMAD2 SMAD family member 2 TGGACACAGGCTCTCCAGCAGAACT

ATPase, H+ transporting,

ASSAY0176 lysosomal 42kDa, V1

Hs00184625 ml ATP6V1 C1 subunit C1 ACCTTCCTGGAATCTCTCTTGATTT coiled-coil domain

ASSAY0210

Hs00203291 ml CCDC106 containing 106 CTCGGATGGAGGCAGAGGACCACTG lysine (K)-specific

ASSAY0225

Hs00218331 ml KDM3A demethylase 3A TTCTT AAAAAG G TATC AG A AG AG C A tankyrase, TRF1 -interacting

ASSAY0230 ankyrin-related ADP-ribose

Hs00228829 ml TNKS2 polymerase 2 TGAAACAGCATTGCATTGTGCTGCT

ASSAY0242 Hs00276830 ml RUNDC2A RUN domain containing 2A CAGTGAAACAGTGCCAGATCCGCTT tetratricopeptide repeat

ASSAY0245

Hs00326671 ml TTC14 domain 14 AGAGAGAGGAGGACAGTTAGAAGAA

ASSAY0256 Hs00385050 ml RNF166 ring finger protein 166 GCGGCCACACGTTCTGCGGGGAGTG

ASSAY0257 DnaJ (Hsp40) homolog,

Hs00397335 ml DNAJC13 subfamily C, member 13 GGTCCAAAGGTTCGAATTACGTTAA _ 1 ΊΑ _

LysM, putative

ASSAY0258 peptidoglycan-binding,

Hs00406040 ml LYSMD3 domain containing 3 TTGTACGGTAGCAGATATCAAGAGA

ASSAY0263 Hs00606262 g1 HDAC1 histone deacetylase 1 AGGAGAAGAAAGAAGTCACCGAAGA

RNA binding motif protein

ASSAY0268

Hs00705337 s1 RBM39 39 AACAGCAGCATATGTACCTCTTCCA

SUB1 homolog (S.

ASSAY0269

Hs00743451 s1 SUB1 cerevisiae) AACTTAATCTCTTCATGTTCAGTTT

ASSAY0274 Hs00963664 g1 UBE3A ubiquitin protein ligase E3A TGGGAGACTCTCACCCAGTTCTATA

Taxi (human T-cell

ASSAY0292 leukemia virus type I)

Hs00195718 ml TAX1 BP1 binding protein 1 AAACAACTCTTGCAGGATGAGAAAG

ASSAY0293 choline/ethanolamine

Hs00196061 ml CEPT1 phosphotransferase 1 ACAGAGCAGGCACCTCTGTGGGCAT polymerase (RNA) III (DNA

ASSAY0299 directed) polypeptide C

Hs00197744 ml POLR3C (62kD) CAGATAACAAGGAGCCCATTCCAGA

NEDD4 binding protein 2-

ASSAY0337

Hs00208459 ml N4BP2L2 like 2 ATTGTCTCGAATTCTGCTTGGTCAG

ASSAY0340 signal-induced proliferation-

Hs00210194 ml SIPA1 L1 associated 1 like 1 ACTAGAGAGGCGGCTGTCTCCTGGT

ASSAY0344 family with sequence

Hs0021 1234 ml FAM164A similarity 164, member A ACATAGCCAGGCCAGATGGGGACTG

ASSAY0352 sirtuin (silent mating type

information regulation 2

Hs00213029 ml SIRT7 homolog) 7 (S. cerevisiae) AATCAGCACGGCAGCGTCTATCCCA

ASSAY0359 Hs00214745 ml DPP8 dipeptidyl-peptidase 8 CTGCCTGCTCCAAGTGATTTCAAGT arginine and glutamate rich

ASSAY0367

Hs00215976 ml ARGLU1 1 AG CCAAACTGG CCG AAG AACAGTTG

ASSAY0369 zinc finger protein 64

Hs00217022 ml ZFP64 homolog (mouse) AGACAATCACAGTTTCAGCTCCAGA

ASSAY0370 Hs00217272 ml NUP133 nucleoporin 133kDa AAC I I I I AAAAGATGGCATTCAGCT

ASSAY0371 chromosome 5 open

Hs00217966 ml C5orf22 reading frame 22 CTTCAAACCCTGGAATGGAATCACT

ASSAY0372 F-box and leucine-rich

Hs00218079 ml FBXL8 repeat protein 8 CACAAAAATCAGTTGCGAATGTGAG

FK506 binding protein 2,

ASSAY0376

Hs00234404 ml FKBP2 13kDa CACTACACGGGGAAGCTGGAAGATG zinc finger, DHHC-type

ASSAY0388

Hs00262263 ml ZDHHC12 containing 12 TGCACGATACCGAGCTGCGGCAATG

ASSAY0401 LSM14A, SCD6 homolog A

Hs00385941 ml LSM14A (S. cerevisiae) GCCCTTGCCAAAGTTCGATCCTTTG

ASSAY0403 similar to solute carrier

Hs00401096 ml SLC35E2 family 35, member E2 TGACTTTCAGCGTCGCCAGCACCGT

ASSAY0407 Hs00540709 s1 TMEM203 transmembrane protein 203 CGGGAGCTGGTGCAGTGGCTAGGCT

ASSAY 0421 Hs00609836 ml AARS alanyl-tRNA synthetase CAAAATTTGGGGCTGGATGACACCA

ASSAY0425 PWP2 periodic tryptophan

Hs00610478 ml PWP2 protein homolog (yeast) GGCTGGCCAAGTACTTCTTCAATAA

ASSAY0429 Hs0061 1 133 ml MRPL10 mitochondrial ribosomal CGCTGCTAGGTGGCTGCATTGATGA protein L10

zinc finger, MYND-type

ASSAY0434

Hs00698392 ml ZMYND17 containing 17 GTGGCGGCATTCCATCCAGG I I I I C

ASSAY0451 Hs00745818 s1 ZNF595 zinc finger protein 595 CAAAGC I I I I AATCGGCCCTCAACC

ASSAY0452 Hs00747351 mH CLTA clathrin, light chain (Lea) GGGGTCCGGATGCTGTTGATGGAGT

ADP-ribosylation factor-like

A8SAYQ456

Hs00750443 s1 ARL8B 8B GTGTGACTCTGTGGGGACTGCATAG

Rho GTPase activating

ASSAY0457

Hs00750732 s1 ARHGAP5 protein 5 TCTACCAATTCTCAGGCACCAAGGG

ASSAY0463 Hs00762481 s1 RPL36 ribosomal protein L36 CCTTCTCCCCGTCGCTGTCCGCAGC

ASSAY0464 Hs00793391 ml CSNK1A1 casein kinase 1 , alpha 1 AG I I I I ATGTAAGGGGTTTCCTGCA

ASSAY0482 methyl-CpG binding

Hs00242770 ml MBD1 domain protein 1 ATTACCAGAGCCCCACAGGAGACAG

ASSAY0486 LSM14B, SCD6 homolog B

Hs00247895 s1 LSM14B (S. cerevisiae) GAGCCTGGGATGAGCCCCGGCAGCG

ASSAY0494 Hs00252433 ml CDC42SE1 CDC42 small effector 1 AGAGCAGGGTTCCGAGTCTGAGGAA

RNA binding motif protein

ASSAY0499 8A;gonadotropin-releasing

RBM8A; hormone (type 2) receptor

Hs00254802 s1 GNRHR2 2 CCCTTCCTTGTCTGGGGCCTGGACA

ASSAY0512 ADP-ribosylation factor

Hs00260786 ml ARFGAP2 GTPase activating protein 2 GTATCCCGAAGCTCTGTCTCCCACT asparagine-linked

ASSAY0521 glycosylation 2, alpha-1 ,3- mannosyltransferase

Hs00263798 ml ALG2 homolog (S. cerevisiae) TAGTGTGCGACCAGGTGTCTGCCTG succinate dehydrogenase

ASSAY0533 complex, subunit B, iron

Hs002681 17 ml SDHB sulfur (Ip) TCATGCAGAGAAGGCATCTGTGGCT

SWI/SNF related, matrix

associated, actin

ASSAY0534 dependent regulator of

chromatin, subfamily c,

Hs00268265 ml SMARCC1 member 1 CCAAACTCCCTGCAAAGTGTTTCAT sortilin-related receptor,

ASSAY0535 L(DLR class) A repeats-

Hs00268342 ml SORL1 containing CAACAAGCGGTACATCTTTGCAGAC

ASSAY0541 Hs00270620 s1 IER2 immediate early response 2 CCCCGCCAAAGTCAGCCGCAAACGA

H3 histone, family 3B

ASSAY0558

Hs00287906 s1 H3F3B (H3.3B) GCTGTATTTGCAGTGTGGGCTAAGA

COMM domain containing

ASSAY0562

Hs00292593 ml COMMD7 7 GGGCGCGCAGCAGTTCTCAGCCCTG

ASSAY0566 Hs00293370 ml SPPL3 signal peptide peptidase 3 TATTTAAAGGGCGACCTCCGGCGGA solute carrier family 38,

ASSAY0568

Hs00298999 ml SLC38A10 member 10 TTCGCCTGCCAGTCCCAGGTGCTGC

SGT1 , suppressor of G2

ASSAY0593 allele of SKP1 (S.

Hs00362511 g1 SUGT1 cerevisiae) CTGCAACATCCCAGAGGTTTTTCCA

ASSAY0603 phosphatidylinositol-3,4,5- trisphosphate-dependent

Hs00368207 ml PREX1 Rac exchange factor 1 CTTCTTGCAGTCGGCATTCCTGCAT

ASSAY061 1 Hs00371424 s1 HIST1 H4D histone cluster 1 , H4d TTCGGCGGCTGAGCTTACCTCTACA _ 1 _

GRB2-associated binding

ASSAY0614

Hs00373045 ml GAB2 protein 2 GAGAGCACAGACTCCCTGAGAAATG translocase of outer

ASSAY0621 mitochondrial membrane

Hs00375641 ml TOMM40L 40 homolog (yeast)-like GCTCAGTCCCACTGAGGTGTTCCCC

ASSAY0625 ubiquitin protein ligase E3

Hs00378208 ml UBR4 component n-recognin 4 CACTTGCTTGG C AAG AC AC AAC ACT

ASSAY0632 chromosome 1 open

Hs00379295 ml C1 orf144 reading frame 144 AACCCATCCTCGACAGGCCAACCAG

ASSAY0638 prolyl-tRNA synthetase 2,

Hs00384448 ml PARS2 mitochondrial (putative) GGCTGGGATTGCGGTGCCTGTGCTT

SEC16 homolog A (S.

ASSAY0648

Hs00389570 ml SEC16A cerevisiae) AACCTAAGAAGGGTGAATCCTGGTT

ASSAY0654 fizzy/cell division cycle 20

Hs00393592 ml FZR1 related 1 (Drosophila) ACGATGCCACGCGTCACAGAGATGC jumonji domain containing

ASSAY0661

Hs00405469 ml JMJD1 C 1 C TCAAAAGCAGGAATTCTCAAGAAAT

ASSAY0684 Hs00417273 ml LRRK2 leucine-rich repeat kinase 2 TTTGGCCCTCCTCACTGAGACTATT

ASSAY0686 structural maintenance of

chromosomes flexible

Hs00418955 ml SMCHD1 hinge domain containing 1 AAGGA I I I I AAATGGACAGGAACAG hypothetical protein

ASSAY0689

Hs00419820 g1 LOC728975 LOC728975 CTGCGTGACCTTGGGCTCTCAGCCC pre-B-cell leukemia

ASSAY0703 homeobox interacting

Hs00430402 ml PBXIP1 protein 1 ACCCCCAAAGCAGCTTGGATCAGGG

ASSAY0709 mitochondrial GTPase 1

Hs00536594 ml MTG1 homolog (S. cerevisiae) CAGCGCTTTGGGTACGTGCAGCACT

ASSAY0710 Hs00536891 ml ITSN2 intersectin 2 GCTATGAATGGAGGGCCAAACATGT

ASSAY0714 Hs00538879 s1 LUC7L3 LUC7-like 3 (S. cerevisiae) GTTACACTCAATGCAATTCTCAAGT deltex homolog 2

ASSAY0718

Hs00539707 ml DTX2 (Drosophila) GGCCGCAAGGTCCTAGAGCTCCTGA dynein, light chain, LC8-

ASSAY0719

Hs00540753 ml DYNLL2 type 2 GCCTCCGTGAAGTGTCACACCATGT coiled-coil domain

ASSAY0720

Hs00540812 ml CCDC101 containing 101 AGAGGCTGAGTGCAACATCCTTCGG

ASSAY0726 Hs00543883 s1 HIST1 H4C histone cluster 1 , H4c TATGGCTTCGGCGGCTGAATCTAAG mitochondrial ribosomal

ASSAY0740

Hs00606809 g1 MRPL41 protein L41 TCCGGTCCAGGGCGCGGCATGGGCG

ASSAY0748 Hs00830558 g1 FOXN3 forkhead box N3 TCTAGGGACTTGGTGTTGCTTGGAA

ASSAY0753 Hs00855332 g1 LDHA lactate dehydrogenase A TCTGACGCACCACTGCCAATGCTGT deleted in lymphocytic

ASSAY0754 leukemia 2 (non-protein

Hs00867656 s1 DLEU2 coding) AAAAATTTA I I I I ACACATGTCAAG ribosomal protein L32

ASSAY0758

Hs00898410 g1 RPL32P3 pseudogene 3 GCTGGCAGGCACCATGTCGTCCTGT

ASSAY0782 Hs00945401 ml ANXA1 annexin A1 TGCCAAGCCATCCTGGATGAAACCA

ASSAY0820 actin related protein 2/3

HsO-1031740 ml ARPC2 complex, subunit 2, 34kDa TGAAAACAATCACGGGGAAGACGTT

ASSAY0827 Hs01037385 s1 HMGB1 high-mobility group box 1 AAAG C AAAG G G AG G ATAAA AC AGTA

ASSAY0835 Hs01053640 ml TXK TXK tyrosine kinase GCTGGCATGAGAAACCTGAAGGCCG _ 1 11 _

non-protein coding RNA

ASSAY0836

Hs01053867 s1 NCRNA00203 203 AGCGCCAGTGCTGGCATGGGCTTTC serine threonine kinase 39

ASSAY0856 (STE20/SPS1 homolog,

Hs01085351 ml STK39 yeast) TAAGTTGGCTTCTGGCTGTGATGGG

U2AF homology motif

ASSAY0869

Hs01 1 1 1764 ml UHMK1 (UHM) kinase 1 ATCCTGGCAGAGGACAAGTCTTTGT

ASSAY0886 Hs01564142 ml GLIPR1 GLI pathogenesis-related 1 CTATACATGACTTGGGACCCAGCAC coiled-coil domain

ASSAY0899

Hs01632947 g1 CCDC72 containing 72 GGAATTAAGTGTTGTCTTGGAGCTG signal recognition particle

ASSAY0900

Hs01636043 s1 SRP9 9kDa TGCTGTTGTGACCAATAAATATAAA

ASSAY0904 Hs01885851 s1 LTB4R2 leukotriene B4 receptor 2 CTACGGCCTTGGCCTTCTTCAGTTC

COMM domain containing

ASSAY0912

Hs01932078 s1 COMMD6 6 AGATTAAGATTGACCATTGCTCCTT dihydropyrimidine

ASSAY0919

Hs02510591 s1 DPYD dehydrogenase GATGGGTGTACAAACTCATCCTCTT

ASSAY0923 tumor necrosis factor,

Hs02621508 s1 TNFAIP8 alpha-induced protein 8 AAATACAGATGTCTCCAGACCTGAG

ASSAY0962 dehydrogenase/reductase

Hs0021 1306 ml DHRS7 (SDR family) member 7 CTTTAAGAGTGGTGTGGATGCAGAC

ASSAY0966 Hs00323799 ml RNF160 ring finger protein 160 TGAAAAGGCATGTCCTAGTTCAGAT

ASSAY1024 cold shock domain

Hs00918650 ml CSDE1 containing E1 , RNA-binding TAAAAGTAGGAGATGATGTTGAATT solute carrier family 39

ASSAY1035 (zinc transporter), member

Hs00202392 ml SLC39A6 6 CGGAGACGAAGGCGCAATGGCGAGG

TAF6 RNA polymerase II,

ASSAY1039 TATA box binding protein

(TBP)-associated factor,

Hs00425763 ml TAF6 80kDa GAGCCTCCTGCTGAAACACTGTGCT

ASSAY1055 eukaryotic translation

Hs00154952 ml EIF4G2 initiation factor 4 gamma, 2 TGCTGGCAACAGCGAGTTCCTGGGG

ASSAY1079 Hs00162564 ml TARS threonyl-tRNA synthetase CGAGGAGAAGCCGATTGGTGCTGGT

ASSAY"! 084 ubiquitin protein ligase E3

Hs00390223 ml UBR4 component n-recognin 4 ACATGACCACAGGTACAGAATCAGA

CTD (carboxy-terminal

ASSAY1099 domain, RNA polymerase

II, polypeptide A) small

Hs00428461 ml CTDSP2 phosphatase 2 CTCACCAAGCAAGGCCTGGTCTCCA

5-nucleotidase domain

ASSAY1 104

Hs00261330 s1 NT5DC1 containing 1 CATATCGATGCATGCAATGGAAAGA Table 22: Informative probes for discriminating between dementia resulting from

Alzheimer's disease and other dementias, such as resulting from other diseases or

conditions (All probes have p-value <0.1 )

Sequence No.

(DiaGenic Gene

Probe ID) Taqman Assay ID Symbol Gene name Context Sequence (Oligonucleotide sequence)

ASSAY0137 Hs99999908_m1 GUSB glucuronidase, beta

TGAACAGTCACCGACGAGAGTGCTG

ASSAY0146 Hs99999903_m 1 ACTB actin, beta GCCTCGCCTTTGCCGATCCGCCGCCCGTCCA

ASSAY0188 Hs00762234_s1 SSNA1 Sjogrens syndrome AGAGGGGCAGGTGCCAGCCTCCACTGGCATC nuclear autoantigen 1

ASSAY0205 Hs00188277_m1 KD 5C Lysine (K)-specific CCACCCGCGGACTGGCAGCCACCCT

demethylase 5C

ASSAY0208 Hs00199477_m 1 SFRS5 splicing factor, GTCAGCTGGCAGGATCTCAAAGATTTCA

arginine/serine-rich 5

ASSAY0209 Hs00200082 ml UBL3 ubiquitin-like 3 CAATTGGCCAATGGACTGGGAAGAA

Coiled-coil domain

ASSAY0210

Hs00203291 ml CCDC106 containing 106 CTCGGATGGAGGCAGAGGACCACTG

family with sequence

ASSAY0214

Hs00207230 ml FAM38A similarity 38, member A CGGCCCTGTGCATTGATTATCCCTG

kinesin family member

ASSAY0216

Hs00209573 ml KIF13B 13B TGCCAACAGGAAGCGAGGCTCTCTT

baculoviral IAP repeat-

ASSAY0218

Hs00212288 ml BIRC6 containing 6 (apollon) GCGAATGCATTCAGGAGCAAGAAGA

ASSAY0223 Hs00215938 ml RNF31 ring finger protein 31 TGCCCCACAACCGGATGCAGGCCCT

Lysine (K)-specific

ASSAY0225 Hs00218331 ml KDM3A demethylase 3A TTCTTAAAAAGGTATCAGAAGAGCA

ASSAY0229 Hs00228149_m 1 BXDC5 brix domain containing CCCTAATGATGAAGAGGTCGCTTATGATGAA

5

tankyrase, TRF1-

ASSAY0230 Hs00228829_m1 TNKS2 interacting ankyrin-related TGAAACAGCATTGCATTGTGCTGCT

ADP-ribose polymerase 2

ASSAY0246 Hs00330168_m1 DNHD1 Dynein heavy chain GGGCGCTGGAGTCAAGTGACTCTAA

domain 1

ASSAY0250 Hs00363005_m1 SCRIB scribbled homolog ACGGAGAACCTGCTGATGGCCCTGC

(Drosophila)

golgin A8 family, member

ASSAY0251 Hs00367259 m GOLGA8B; B;golgin A8 family, AGAAGCCGGATGGGTTCTCGAGCCG

1 GOLGA8A member A

ASSAY0254 Hs00382453_m1 XP05 exportin 5 TTGCGCTTATAAGAACCCACAATAC

ASSAY0259 Hs00415782_m1 TMEM179B transmembrane protein CTCGGACCCAGGGCTCCTTCAGTGG

179B

DEAD (Asp-Glu-Ala-

ASSAY0260 Hs00428123_m 1 DDX23 Asp) box polypeptide AAATCTG CAG AAAG AG AAC G ACG G CACAAA

23

ASSAY0264 Hs00606522 ml TARDBP TAR DNA binding protein GAGAAGTTCTTATGGTGCAGGTCAA SH3 domain binding

ASSAY0265 Hs00606772_g1 SH3BGRL3 glutamic acid-rich protein CACCGGCTCCCGCGAAATCAAGTCC like 3

SUB1 homolog (S.

ASSAY0269

HS00743451 s1 SUB1 cerevisiae) AACTTAATCTCTTCATGTTCAGTTT

protein tyrosine

ASSAY0270 Hs00754750_s1 PTP4A2 phosphatase type IVA, CC I I I I CCCCCGATCCAAGTTGTAG

member 2

phosphatidylethanolamine

ASSAY0272

Hs00831506 g1 PEBP1 binding protein 1 TGGCAAATTCAAGGTGGCGTCCTTC

dm4 p53 binding protein

ASSAY0273

Hs00910358 s1 MDM4 homolog (mouse) TGCATTCTTGCCTAG I I I I CCTTAT

Ubiquitin protein ligase

ASSAY0274

Hs00963664 g1 UBE3A E3A TGGGAGACTCTCACCCAGTTCTATA

Not

ASSAY0276 Hs01020041_s1 available Not available TACTGGGCGCTGGCGAAGGGCCTGGCTCC

Sequences corresponding to Assay Nos (sequence numbers) are provided in the Sequence

Listing below. The following Table provides the SEQ ID NO: of each of the sequences that correspond to the Assay Nos. The context sequences (oligonucleotide sequences) reported in the above tables appear within the sequences.

ASSAY NO SEQ ID NO. ASSAY NO SEQ ID NO. ASSAY NO SEQ ID NO.

ASSAY0001 1 ASSAYO 084 55 ASSAY0155 108

ASSAY0002 2 ASSAYO 085 56 ASSAYO156 109

ASSAY0003 3 ASSAYO 086 57 ASSAY0157 110

ASSAY0006 4 ASSAYO 087 58 ASSAY0158 111

ASSAY0007 5 ASSAYO 088 59 ASSAY0159 112

ASSAY0010 6 ASSAYO 089 60 ASSAY0160 113

ASSAY0011 7 ASSAYO 092 61 ASSAY0161 114

ASSAY0012 8 ASSAYO 093 62 ASSAY0162 115

ASSAY0013 9 ASSAYO 096 63 ASSAY0163 116

ASSAY0014 10 ASSAYO 097 64 ASSAY0164 117

ASSAY0015 11 ASSAY0098 65 ASSAY0165 118

ASSAY0017 12 ASSAYO 099 66 ASSAY0166 119

ASSAY0018 13 ASSAYO 103 67 ASSAY0168 120

ASSAYO 020 14 ASSAYO 104 68 ASSAY0169 121

ASSAY0022 15 ASSAYO 107 69 ASSAYO170 122

ASSAYO 024 16 ASSAYO 108 70 ASSAYO171 123

ASSAYO 027 17 ASSAY0110 71 ASSAY0172 124

ASSAYO 031 18 ASSAYO 112 72 ASSAYO174 125

ASSAYO 032 19 ASSAYO 113 73 ASSAYO176 126

ASSAYO 036 20 ASSAYO 114 74 ASSAYO178 127

ASSAYO 037 21 ASSAYO 115 75 ASSAYO179 128

ASSAYO 038 22 ASSAYO 116 76 ASSAY0180 129

ASSAYO 039 23 ASSAYO 117 77 ASSAY0181 130

ASSAYO 040 24 ASSAYO 118 78 ASSAY0182 131

ASSAYO 041 25 ASSAYO 119 79 ASSAY0183 132

ASSAYO 044 26 ASSAYO 120 80 ASSAY0184 133

ASSAYO 045 27 ASSAYO 122 81 ASSAY0185 134

ASSAYO 046 28 ASSAYO123 82 ASSAY0186 135

ASSAYO 047 29 ASSAYO 124 83 ASSAY0187 136

ASSAYO 048 30 ASSAYO 126 84 ASSAY0188 780

ASSAYO 049 31 ASSAYO 127 85 ASSAY0189 137

ASSAYO 050 32 ASSAYO 128 86 ASSAY0190 138

ASSAYO 051 33 ASSAYO 129 87 ASSAY0191 139

ASSAY0052 34 ASSAY0132 88 ASSAY0193 140

ASSAYO 053 35 ASSAYO 133 89 ASSAY0194 141

ASSAYO 054 36 ASSAYO 135 90 ASSAY0195 142

ASSAYO 055 37 ASSAYO 136 91 ASSAY0196 143

ASSAYO 056 38 ASSAYO 137 92 ASSAY0197 144

ASSAYO 057 39 ASSAYO 138 93 ASSAY0198 145

ASSAYO 060 40 ASSAYO 139 94 ASSAY0199 146

ASSAYO 061 41 ASSAYO 140 95 ASSAYO200 147

ASSAYO 062 42 ASSAYO 141 96 ASSAY0202 148

ASSAYO 063 43 ASSAYO 142 97 ASSAY0203 149

ASSAYO 065 44 ASSAYO 144 98 ASSAYO204 150

ASSAYO 066 45 ASSAYO 145 99 ASSAY0205 151

ASSAYO 067 46 ASSAYO 146 779 ASSAYO206 152

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ASSAY0478 348 ASSAYO549 402 ASSAYO 621 455

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ASSAY0481 351 ASSAY0552 405 ASSAY0625 458

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ASSAYO 484 354 ASSAYO558 407 ASSAYO 628 461

ASSAYO 485 355 ASSAYO559 408 ASSAYO 629 462

ASSAYO 486 356 ASSAYO560 409 ASSAYO 632 463

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ASSAYO 491 360 ASSAYO565 413 ASSAYO 638 467

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ASSAY0653 479 ASSAY0722 533 ASSAY0802 587

ASSAY065 480 ASSAY0723 534 ASSAY0804 588

ASSAY0655 481 ASSAY0724 535 ASSAY0805 589

ASSAYO 656 482 ASSAY0725 536 ASSAY0806 590

ASSAY0657 483 ASSAYO726 537 ASSAY0807 591

ASSAYO 659 484 ASSAY0727 538 ASSAY0809 592

ASSAYO 660 485 ASSAY0728 539 ASSAY0810 593

ASSAYO 661 486 ASSAYO729 540 ASSAY0811 594

ASSAYO 662 487 ASSAYO733 541 ASSAY081 595

ASSAYO 664 488 ASSAY0734 542 ASSAY0817 596

ASSAYO 665 489 ASSAY0736 543 ASSAY0818 597

ASSAYO 666 490 ASSAY0739 544 ASSAYO819 598

ASSAYO 667 491 ASSAY0740 545 ASSAYO820 599

ASSAYO 668 492 ASSAY0741 546 ASSAYO821 600

ASSAYO 669 493 ASSAY0743 547 ASSAY0822 601

ASSAYO 670 494 ASSAY0744 548 ASSAYO826 602

ASSAYO 671 495 ASSAY0745 549 ASSAYO827 603

ASSAYO 672 496 ASSAY0746 550 ASSAYO831 604

ASSAYO 673 497 ASSAY0748 551 ASSAYO833 605

ASSAY0674 498 ASSAY0749 552 ASSAY0834 606

ASSAYO 675 499 ASSAY0750 553 ASSAY0835 607

ASSAYO 676 500 ASSAY0751 554 ASSAYO836 608

ASSAYO 677 501 ASSAYO752 555 ASSAYO838 609

ASSAYO 678 502 ASSAYO753 556 ASSAY0841 610

ASSAYO 679 503 ASSAY0754 557 ASSAY0842 611

ASSAYO 682 504 ASSAYO755 558 ASSAY0843 612

ASSAYO 683 505 ASSAY0756 559 ASSAY0844 613

ASSAYO 684 506 ASSAY0758 560 ASSAYO846 614

ASSAYO 686 507 ASSAY0759 561 ASSAY0847 615

ASSAYO 687 508 ASSAY0760 562 ASSAYO850 616

ASSAYO 689 509 ASSAY0762 563 ASSAY0853 617

ASSAYO 691 510 ASSAY0763 564 ASSAYO854 618

ASSAYO 692 511 ASSAY0766 565 ASSAYO856 619

ASSAYO 693 512 ASSAY0767 566 ASSAYO857 620

ASSAYO 695 513 ASSAY0771 567 ASSAYO858 621

ASSAYO 696 514 ASSAY0772 568 ASSAY0859 622

ASSAYO 697 515 ASSAY0773 569 ASSAY0861 623

ASSAYO 698 516 ASSAY0774 570 ASSAYO862 624

ASSAYO 699 517 ASSAY0778 571 ASSAYO863 625

ASSAY0701 518 ASSAY0780 572 ASSAYO865 626

ASSAYO702 519 ASSAY0781 573 ASSAY0866 627

ASSAYO703 520 ASSAYO782 574 ASSAY0867 628

ASSAY0704 521 ASSAY0784 575 ASSAY0869 629

ASSAY0706 522 ASSAYO785 576 ASSAYO871 630

ASSAY0709 523 ASSAY0786 577 ASSAYO874 631

ASSAY0710 524 ASSAY0790 578 ASSAYO876 632

ASSAY0712 525 ASSAY0792 579 ASSAY0878 633

ASSAY0713 526 ASSAY0793 580 ASSAYO879 634

ASSAY0714 527 ASSAY0794 581 ASSAY0882 635

ASSAY0715 528 ASSAY0795 582 ASSAY0883 636

ASSAY0716 529 ASSAY0797 583 ASSAY0885 637

ASSAY0718 530 ASSAYO798 584 ASSAY0886 638

ASSAY0719 531 ASSAY0799 585 ASSAY0887 639

ASSAY0720 532 ASSAYO 801 586 ASSAY0888 640 ASSAY NO SEQ ID NO. ASSAY NO SEQ ID NO. ASSAY NO SEQ ID NO.

ASSAYO 893 641 ASSAYO 982 695 ASSAY1063 749

ASSAYO 894 642 ASSAYO 983 696 ASSAY1064 750

ASSAY0895 643 ASSAYO 985 697 ASSAY1065 751

ASSAYO 897 644 ASSAYO 986 698 ASSAY1066 752

ASSAYO 899 645 ASSAYO 987 699 ASSAY1071 753

ASSAYO 900 646 ASSAYO 988 700 ASSAY1074 754

ASSAYO 903 647 ASSAYO 990 701 ASSAY1075 755

ASSAYO 90 648 ASSAYO 992 702 ASSAY1077 756

ASSAYO 906 649 ASSAYO 994 703 ASSAY1078 757

ASSAYO 907 650 ASSAYO 996 704 ASSAY1079 758

ASSAYO 910 651 ASSAYO 997 705 ASSAY1081 759

ASSAYO 911 652 ASSAYO 998 706 ASSAY1082 760

ASSAYO 912 653 ASSAY1000 707 ASSAY1083 761

ASSAYO 913 654 ASSAY1001 708 ASSAY1084 762

ASSAYO 914 655 ASSAY1002 709 ASSAY1086 763

ASSAYO 916 656 ASSAY1004 710 ASSAY1087 764

ASSAYO 917 657 ASSAY1006 711 ASSAY1088 765

ASSAYO 919 658 ASSAY1007 712 ASSAY1090 766

ASSAYO 921 659 ASSAY1010 713 ASSAY1093 767

ASSAYO 922 660 ASSAY1011 714 ASSAY1094 768

ASSAYO 923 661 ASSAY1012 715 ASSAY1095 769

ASSAYO 924 662 ASSAY1014 716 ASSAY1096 770

ASSAYO 925 663 ASSAY1017 717 ASSAY1097 771

ASSAYO 927 664 ASSAY1018 718 ASSAY1099 772

ASSAYO 928 665 ASSAY1019 719 ASSAY1100 773

ASSAYO 929 666 ASSAY1022 720 ASSAY1101 774

ASSAYO 931 667 ASSAY1023 721 ASSAY1102 775

ASSAYO 933 668 ASSAY1024 722 ASSAY1103 776

ASSAYO 934 669 ASSAY1025 723 ASSAY1104 777

ASSAYO 935 670 ASSAY1026 724

ASSAYO 936 671 ASSAY1029 725

ASSAYO 938 672 ASSAY1030 726

ASSAYO 939 673 ASSAY1033 727

ASSAYO 941 674 ASSAY1035 728

ASSAYO 943 675 ASSAY1036 729

ASSAYO 944 676 ASSAY1037 730

ASSAYO 947 677 ASSAY1039 731

ASSAYO 948 678 ASSAY1040 732

ASSAYO 950 679 ASSAY1041 733

ASSAYO 951 680 ASSAY1042 734

ASSAYO 953 681 ASSAY1044 735

ASSAYO 957 682 ASSAY1045 736

ASSAYO 959 683 ASSAY1046 737

ASSAYO 960 684 ASSAY1047 738

ASSAYO 962 685 ASSAY1048 739

ASSAYO 964 686 ASSAY1051 740

ASSAYO 966 687 ASSAY1052 741

ASSAYO 968 688 ASSAY1053 742

ASSAYO 969 689 ASSAY1055 743

ASSAYO 970 690 ASSAY1056 744

ASSAYO 971 691 ASSAY1057 745

ASSAYO 976 692 ASSAY1058 746

ASSAYO 978 693 ASSAY1059 747

ASSAYO 980 694 ASSAY1061 748

Claims

Claims:

1. A set of oligonucleotide probes, wherein said set comprises at least 10

oligonucleotides, wherein each of said 10 oligonucleotides, which are each different, are selected from:

(a) an oligonucleotide which is a part of a sequence as set forth in any one of Tables

I to 1 1 and 22, preferably Tables 1 to 9;

(b) an oligonucleotide derived from a sequence as set forth in any one of Tables 1 to

I I and 22, preferably Tables 1 to 9;

(c) an oligonucleotide with a sequence complementary to the sequence of the oligonucleotide of a) or b); or

(d) an oligonucleotide which is functionally equivalent to an oligonucleotide as defined in (a), (b) or (c).

2. A set as claimed in claim 1 wherein said set comprises at least 30 oligonucleotides selected from a) to d).

3. A set as claimed in claim 1 or 2 wherein said set comprises oligonucleotides from all of the sequences set forth in any one of Tables 1 to 1 1 and 22, preferably Tables 1 to 9, or derived, complementary or functionally equivalent oligonucleotides thereof.

4. A set as claimed in any one of claims 1 to 3 wherein said oligonucleotide in (a) is all or a part of the oligonucleotide sequence as set forth in any one of Tables 2 to 1 1 and 22, preferably Tables 2 to 9.

5. A set of oligonucleotide probes as claimed in any one of claims 1 to 5, wherein each probe in said set binds to a different transcript.

6. A set as claimed in any one of claims 1 to 5, wherein said set comprises at least 20 oligonucleotides and said set comprises pairs of primers in which each oligonucleotide in said pair of primers binds to the same transcript or its complementary sequence and preferably each of the pairs of primers bind to a different transcript.

7. A set of oligonucleotide probes as claimed in any one of claims 1 to 5, wherein said set comprises at least 30 oligonucleotides and said set comprises pairs of primers and a labelled probe for each pair of primers in which each oligonucleotide in said pair of primers and said labelled probe bind to the same transcript or its complementary sequence and preferably each of the pairs of primers and the labelled probe bind to different transcripts.

8. A set as claimed in any one of claims 1 to 7 wherein said at least 10 oligonucleotides selected from a) to d) comprise oligonucleotides from all of the sequences set forth in Table 3, or derived, complementary or functionally equivalent oligonucleotides thereof and oligonucleotides selected from a) to d) from sequences set forth in Table 2 which exhibit a p- value of <0.5, or derived, complementary or functionally equivalent oligonucleotides thereof.

9. A set as claimed in any one of claims 1 to 7 wherein said at least 10 oligonucleotides selected from a) to d) comprise oligonucleotides from sequences which are set forth in both Tables 2 and 3 (or Tables 9 and 10) or derived, complementary or functionally equivalent oligonucleotides thereof.

10. A set as claimed in any one of claims 1 to 9 consisting of from 10 to 500

oligonucleotide probes.

1 1 . A set of oligonucleotide probes as claimed in any one of claims 1 to 10, wherein each of said oligonucleotide probes is from 15 to 200 bases in length.

12. A set of oligonucleotide probes as claimed in any one of claims 1 to 1 1 , wherein said probes are immobilized on one or more solid supports.

13. A set of oligonucleotide probes as claimed in claim 12, wherein said solid support is a sheet, filter, membrane, plate or biochip.

14. A kit comprising a set of oligonucleotide probes as defined in claim 12 or 13 preferably immobilized on one or more solid supports.

15. A kit as claimed in claim 14 wherein said probes are immobilized on a single solid support and each unique probe is attached to different region of said solid support.

16. A kit as claimed in claim 14 or 15 further comprising standardizing materials.

17. The use of a set of oligonucleotide probes as defined in any one of claims 1 to 13 or a kit as defined in any one of claims 14 to 16 to determine the gene expression pattern of a cell or sample where the pattern reflects the level of gene expression of genes to which said oligonucleotide probes bind, comprising at least the steps of:

a) isolating mRNA from said cell or sample, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotide probes or a kit as defined herein; and

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce said pattern,

wherein the oligonucleotides in said set of oligonucleotides or kit are primary

oligonucleotides and said set or kit may additionally comprise secondary oligonucleotides which are not assessed in step c).

18. A method of preparing a standard gene transcript pattern characteristic of a neurological disease or condition with a specific stage or progression profile in an organism comprising at least the steps of:

a) isolating mRNA from a blood sample (e.g containing cells) of one or more organisms having said neurological disease or condition with a specific stage or progression profile, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit as defined in claim 17 specific for said neurological disease or condition with a specific stage or progression profile in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce a characteristic pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in the sample with said neurological disease or condition with a specific stage or progression profile.

19. A method of preparing a test gene transcript pattern comprising at least the steps of: a) isolating mRNA from a blood sample (e.g. containing cells) of said test organism, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit as defined in claim 17 specific for a specific stage or progression profile of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce said pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in said test sample.

20. A method of diagnosing or identifying or monitoring a specific stage or progression profile of a neurological disease or condition in an organism, comprising the steps of:

a) isolating mRNA from a blood sample (e.g. containing cells) of said organism, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit as defined in claim 17 specific for a specific stage or progression profile of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation;

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce a characteristic pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in said sample; and

d) comparing said pattern to a standard diagnostic pattern prepared according to claim 18 using a sample from an organism corresponding to the organism and sample under investigation to determine the degree of correlation indicative of the presence of a specific stage or progression profile of a neurological disease or condition in the organism under investigation.

21 . A method of diagnosing or identifying a specific progression profile of a neurological disease or condition in an organism, comprising the steps of:

a) isolating mRNA from a blood sample (e.g. containing cells) of said organism, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit comprising oligonucleotides specific for a specific progression profile of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation;

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce a characteristic pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in said sample; and d) comparing said pattern to a standard diagnostic pattern prepared according to claim 18 using a sample from an organism corresponding to the organism and sample under investigation and a set of oligonucleotides or a kit as defined in step b) to determine the degree of correlation indicative of the presence of a specific progression profile of a neurological disease or condition in the organism under investigation.

22. A method of determining the efficacy of a treatment of a neurological disease or condition in an organism, comprising performing steps of a) to d) of the method of claim 20, before, during, and/or after treatment of said neurological condition or disease in said organism to determine the efficacy of said treatment.

23. A method of monitoring the progression of a neurological disease or condition in an organism, comprising the steps of:

a) isolating mRNA from a blood sample (e.g. containing cells) of said organism, which may optionally be reverse transcribed to cDNA;

b) hybridizing the mRNA or cDNA of step (a) to a set of oligonucleotides or a kit as claimed in claim 17 specific for a specific stage of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation;

c) assessing the amount of mRNA or cDNA hybridizing to each of said probes to produce a characteristic pattern reflecting the level of gene expression of genes to which said oligonucleotides bind, in said sample;

d) comparing said pattern to a standard diagnostic pattern prepared according to claim 18 using a sample from an organism corresponding to the organism and sample under investigation to determine the degree of correlation indicative of the specific stage of a neurological disease or condition in the organism under investigation;

e) after a time interval, repeating steps a) to d);

f) comparing the specific stage of the disease or condition identified before and after the time interval to establish the progression of said disease or condition.

24. A use or method as claimed in any one of claims 17 to 23 wherein said probes are primers and in step b) said mRNA or cDNA or a part thereof is amplified using said primers and in step c) the amount of amplified product is assessed to produce said pattern.

25. A use or method as claimed in any one of claims 17 to 24 wherein said probes are labelling probes and pairs of primers and in step b) said labelling probes and primers are hybridized to said mRNA or cDNA and said mRNA or cDNA or a part thereof is amplified using said primers, wherein when said labelling probe binds to the target sequence it is displaced during amplification thereby generating a signal and in step c) the amount of signal generated is assessed to produce said pattern.

26. A use or method as claimed in any one of claims 17 to 25 wherein said mRNA or cDNA is amplified prior to step b).

27. A use or method as claimed in any one of claims 17 to 26 wherein the oligonucleotides and/or the mRNA or cDNA are labelled.

28. A use or method as claimed in any one of claims 17 to 27 wherein said pattern is expressed as an array of numbers relating to the expression level associated with each probe.

29. A method of identifying a compound suitable for the treatment of a

neurodegenerative condition or disease or a specific stage or progression profile thereof in an organism comprising the steps of:

a) identifying the stage or progression profile of said organism by the method of claim 20 or 21 ,

b) administering said compound to said organism,

c) repeating step a) after step b),

d) comparing the stages or progression profiles identified in steps a) and c) to determine if any therapeutic benefit is observed in said organism relative to a comparable organism not treated by said compound.

30. A method of preparing a standard gene transcript expression pattern characteristic of a neurological disease or condition with a specific stage or progression profile in an organism comprising at least the steps of:

a) releasing target polypeptides from a sample of one or more organisms having said neurological disease or condition with a specific stage or progression profile;

b) contacting said target polypeptides with one or more binding partners, preferably at least 10 binding partners, wherein each binding partner is specific to a marker polypeptide (or a fragment thereof) encoded by the gene to which an oligonucleotide probe as defined in claim 1 binds, to allow binding of said binding partners to said target polypeptides, wherein said marker polypeptides are specific for said neurological disease or condition with a specific stage or progression profile in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and

c) assessing the target polypeptide binding to said binding partners to produce a characteristic pattern reflecting the level of gene expression of genes which express said marker polypeptides, in the sample with said neurological disease or condition with a specific stage or progression profile.

31 . A method of preparing a test gene transcript expression pattern comprising at least the steps of:

a) releasing target polypeptides from a sample of said test organism;

b) contacting said target polypeptides with one or more binding partners, preferably at least 10 binding partners, wherein each binding partner is specific to a marker polypeptide (or a fragment thereof) encoded by the gene to which an oligonucleotide probe as defined in claim 1 binds, to allow binding of said binding partners to said target polypeptides, wherein said marker polypeptides are specific for a specific stage or progression profile of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and

c) assessing the target polypeptide binding to said binding partners to produce a characteristic pattern reflecting the level of gene expression of genes which express said marker polypeptides, in said test sample.

32. A method of diagnosing or identifying or monitoring a specific stage or progression profile of a neurological disease or condition in an organism comprising the steps of:

a) releasing target polypeptides from a sample of said organism;

b) contacting said target polypeptides with one or more binding partners, preferably at least 10 binding partners, wherein each binding partner is specific to a marker polypeptide (or a fragment thereof) encoded by the gene to which an oligonucleotide probe as defined in claim 1 binds, to allow binding of said binding partners to said target polypeptides, wherein said marker polypeptides are specific for a specific stage or progression profile of a neurological disease or condition in an organism and sample thereof corresponding to the organism and sample thereof under investigation; and c) assessing the target polypeptide binding to said binding partners to produce a characteristic pattern reflecting the level of gene expression of genes which express said marker polypeptides in said sample; and

d) comparing said pattern to a standard diagnostic pattern prepared according to claim 30 using a sample from an organism corresponding to the organism and sample under investigation to determine the degree of correlation indicative of the presence of a specific stage or progression profile of a neurological disease or condition in the organism under investigation.

33. A method as claimed in any one of claims 18 to 32 wherein said organism is a eukaryotic organism, preferably a mammal.

34. A method as claimed in claim 33 wherein said organism is a human.

35. A use or method as claimed in any one of claims 17 to 34 wherein the data making up said pattern is mathematically projected onto a classification model.

36. A use or method as claimed in any one of claims 17 to 35 wherein said sample is peripheral blood.

37. A method as claimed in any one of claims 18 to 30 or 32 to 36 wherein said neurological disease or condition is Alzheimer's disease.

38. A method as claimed in any one of claims 18 to 30 or 32 to 36 wherein said neurological disease or condition is MCI.

39. A method as claimed in any one of claims 18 to 30 or 32 to 37 wherein said stage of said neurological disease or condition is prodromal Alzheimer's disease.

40. A method as claimed in any one of claims 18 to 30, 32 to 36 or 38 wherein said stage of said neurological disease or condition is stable MCI.

41 . A method as claimed in any one of claims 18 to 30 or 32 to 36 wherein said progression profile of said neurological disease or condition is predictive of clear progression of dementia, preferably Alzheimer's disease.

42. A method as claimed in any one of claims 38 to 40 wherein said probes are from Tables 2, 3, 4 and/or 6.

43. A method as claimed in claim 41 wherein said probes are from Tables 9, 10 and/or 1 1 .

44. A method as claimed in any one of claims 18 to 30 or 32 to 36 wherein said stage of said neurological disorder or condition is Alzheimer's disease associated with dementia, wherein preferably in said method of claims 19 to 21 , 31 or 32, said organism in step a) has a dementia of unknown origin.

45. A method as claimed in claim 44 wherein said probes are from Table 22.