WO2005098725A2 - Utilisation d'algorithmes cliniques actionnes par un systeme expert dans des essais cliniques du systeme nerveux central - Google Patents

Utilisation d'algorithmes cliniques actionnes par un systeme expert dans des essais cliniques du systeme nerveux central Download PDF

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WO2005098725A2
WO2005098725A2 PCT/EP2005/003682 EP2005003682W WO2005098725A2 WO 2005098725 A2 WO2005098725 A2 WO 2005098725A2 EP 2005003682 W EP2005003682 W EP 2005003682W WO 2005098725 A2 WO2005098725 A2 WO 2005098725A2
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crit
symptoms
patient group
data
history
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PCT/EP2005/003682
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WO2005098725A8 (fr
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Erik Buntinx
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B & B Beheer Nv
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
    • G16H10/20—ICT specially adapted for the handling or processing of patient-related medical or healthcare data for electronic clinical trials or questionnaires

Definitions

  • the invention relates to the field of automating diagnosing patients and clinical trials. More specifically, the invention relates to the use of originally developed clinical algorithms via an expert software system to objectify the diagnosis of patients suffering from Central Nervous System (CNS) related diseases, and for the implementation and analysis of clinical trials in the field of the CNS.
  • CNS Central Nervous System
  • diagnoses are made by the use of lists of diagnostic criteria and categories from established classification systems (ICD-10, DSM-IV).
  • the reliability refers to the extent to which clinicians will agree on a specific category as applying to a particular patient.
  • the validity refers to the extent to which the diagnostic category actually reflects specific disease or condition. Making a diagnosis depends on identifying and eliciting the primary clinical data, namely history, symptoms, signs and behaviors. These data will then need to be checked against the list of diagnostic criteria to determine the best fit and hence the most probable diagnosis.
  • most diagnostic criteria and categories from established classification systems are not presented in an optimal way. Unfortunately, most psychiatric textbooks and other sources only provide a systematic overview of diseases according to disorder.
  • the psychiatrist In order to find out to what disorder best matches certain symptoms, the psychiatrist first needs to have an a priori knowledge about which disorder could cause that symptoms, and, secondly, has to find where exactly these disorders are discussed in the book (or other medium), and whether or not the description of the symptoms findings in this reference text indeed corresponds to his "case". Such a search may be quite straightforward in some cases while it may be quite time-consuming and frustrating in others. Also, even the most recently developed databases on the Internet are organized by disorder, not by symptoms. Furthermore, information in most psychiatry textbooks and other references is not structured according to the work flow of the psychiatrist and finding practical information is difficult. For difficult cases, he has to find an appropriate textbook to identify the diseases that may be present with a pattern similar to the one he has identified.
  • the psychiatrist creates a list of possible diagnoses (Diagnosis 1 to n), from which the diseases that do not result in the appropriate pattern are eliminated. This list can further be refined by matching the clinical status of his particular patient with the patient-related information provided for the different diseases. It is clearthat this is a quite inefficient process.
  • Rating scales - often used in the research for new CNS medicaments - are believed to be objective, i.e. valid and reliable with the connotation of scientific, good, above board, not subjective, sellable, better than other approaches, etc., and superior to the happy chat or the clinical interview. There is surprisingly limited evidence for this notion but it survives as a counterpart to the - wrong - view that interviews are subjective.
  • the objective of the rating scale is to measure rapid change in days or weeks. The mystery is why a continuous number can issue out of the arithmetic addition of qualitatt/e decisions.
  • Global scores are summary narratives and cannot be considered as absolute. A 0 score cannot be interpreted as absence of the condition; nor can someone scoring 40 be said to be twice as sick as someone scoring 20.
  • the items used in the diagnostic criteria and rating scales are to fulfill a proxy function and the success of any scale depends on the quality of the proxying. Standardization methods cannot evaluate the proxying function of each item. Items do not measure directly the target clinical state, trait or condition; they measure it indirectly, i.e. they are always mediated by a construct.
  • a construct is a notion or image purporting to map or represent something else; it is thus a semantic structure. The semantic information of a scale is found in the instructions and in the history of the scale but the latter two are rarely consulted and pondered over, for there is the wrong belief that once treated statistically, rating instruments become autonomous entities that do not need to have a past.
  • Behavioral phenocopies are represented by the level at which the psychiatric symptoms and signs (data) are being captured by the clinician and hence identified and named. This gives differences in clinical symptoms, signs and behavior that are simply not being determined by the clinician.
  • the present invention thus relates to a method for evaluating drug efficacy in CNS-related disorders, wherein the effects of trait symptoms on the diagnosis are eliminated or at least decreased or reduced. Also, the present invention relates to objectifying diagnosing patients in CNS-related disorders, wherein the effects of trait symptoms on the diagnosis are eliminated or at least decreased or reduced.
  • the present invention thus relates to a method for evaluating drug efficacy in CNS-related disorders, comprising: (a) providing a patient group diagnosed with a CNS-related disorder,
  • step (c) diagnosing the State Symptoms of said first and said second patient groups, wherein (the effects of) trait symptoms are eliminated or decreased, (d) comparing the results obtained with said first and said second patient groups from step (c), thereby evaluating drug efficacy.
  • a further aspect of the invention relates to a method for evaluating drug efficacy in mood disorders, comprising:
  • step (c) diagnosing the State Symptoms (ST) of each individual patient of said first (AT) and said second (PT) patient groups, wherein trait symptoms (TS) are evaluated comprising: (d) accessing an expert system comprising a database comprising data of symptoms, signs, history, and/or behaviors and disorders associated therewith, (c2) providing data to said expert system on symptoms, signs, history, and/or behaviors of each individual patient of said first (AT) and said second (PT) patient groups, (c2) extracting from the database a list of the severity of the mood disorders corresponding to the symptoms, signs, history, and/or behaviors, wherein trait symptoms are evaluated, (d) comparing the results obtained with said first (AT) and said second (PT) patient groups from step (c), thereby evaluating drug efficacy.
  • a diminishment of the trait symptoms in the total amount of symptoms in a patient group accentuates the efficacy of an active compound relative to a placebo treated group. For instance, a diminishment of the trait symptoms on the total amount of symptoms in a patient group diagnosed with a depressive state from 50 to 10 per cent, the symptom reduction after 8 weeks of treatment with an active compound would be 18 per cent greater than in the placebo treated group. In comparison, till now the mean difference known by meta-analysis of all the main trials for Major Depressive Disorder is 10 per cent, namely a symptom reduction of 40% in the active treated group and of 30% in the placebo treated group (A. Khan et al, Archives of General Psychiatry, Volume 57, April 20O0).
  • ASR-A8WOT-MDD ((0.2*%TS)+(0.6*%ST) of AT) - ((0.2*%TS)+(0.4*%ST) of PT),
  • ASR-A8WOT-MDD stands for Active Symptom Reduction After 8 Weeks Of Treatment
  • %TS stands for percentage of Trait Symptoms in comparison with the total amount of symptoms
  • %ST stands for percentage of State Symptoms
  • AT stands for Active Treatment
  • PT stands for Placebo Treatment.
  • the present invention relates to a method for evaluating drug efficacy in CNS- related disorders, comprising determining the Active Symptom Reduction After 8 Weeks Of Treatment (ASR-A8WOT) comprising:
  • step (d) subtracting the State Symptoms of said second patient group (ST 2 ), wherein trait symptoms are evaluated (TS 2 ) of step (c2), from the State Symptoms of said first patient group (ST-i), wherein trait symptoms are evaluated (TS ⁇ from step (d ), thereby evaluating drug efficacy.
  • the term “State Symptoms” (ST) relates to these symptoms which define the state of the mentioned disorder, i.e. anhedonia.
  • the term “Trait Symptoms” (TS) relates to these symptoms which define the pre-morbid temperament of the examined person, i.e. novelty seeking.
  • the term “Active Treatment” (AT) relates to a treatment with a substance wherein one or more compound(s) are inserted with demonstrated pharmacological mode(s) of action.
  • the term “Placebo Treatment” (PT) relates to a treatment with a substance wherein no compound(s) is inserted with a demonstrated pharmacological mode of action.
  • the present invention relates to a method as described herein, wherein said diagnosing the State Symptoms is based on symptom(s), sign(s), history and/or behavior(s).
  • the method of the present invention relates to diagnosing the State Symptoms by using lists of diagnostic criteria and categories from ICD-10 or DSM-IV. Also, the present invention relates to a method as described herein, wherein said trait symptoms are caused by symptom(s), sign(s), history and/or behavior(s).
  • Table 1 gives a few examples of the effect towards the Added Symptom Reduction depending on the percentage of trait and state symptoms in a patient group.
  • treatment include amelioration or elimination of a developed mental disease or condition once it has been established or alleviation of the characteristic symptoms of such disease or condition.
  • these terms also encompass, depending on the condition of the patient, preventing the onset of a disease or condition or of symptoms associated with a disease or condition, including reducing the severity of a disease or condition or symptoms associated therewith prior to affliction with said disease or condition.
  • prevention or reduction prior to affliction refers to administration of the compound or composition of the invention to a patient that is not at the time of administration afflicted with the disease or condition.
  • Preventing also encompasses preventing the recurrence or relapse-prevention of a disease or condition or of symptoms associated therewith, for instance after a period of improvement. It should be clear that mental conditions may be responsible for physical complaints.
  • treating also includes prevention of a physical disease or condition or amelioration or elimination of the developed physical disease or condition once it has been established or alleviation of the characteristic symptoms of such conditions.
  • immediatecament also encompasses the terms "drug", “therapeutic”, “potion” or other terms which are used in the field of medicine to indicate a preparation with therapeutic or prophylactic effect.
  • diagnosis is well known in the art and relates to the art or act of recognizing the presence of a disorder from its sign(s), history, behavior(s) and/or symptom(s), and deciding as to its character.
  • a concrete application of such an automated checking system is the clinimetric re- engineering of rating scales used in CNS clinical trials. The principles hereof are the ruling out non-specific complaints and/or symptoms ('noise') and the evaluation of the partial or full resolution of 'core' symptoms of examined disorder by ruling out the trait symptoms in baseline and efficacy evaluation.
  • clinical quality measurement rules is well known in the art, and relates to an accepted method for developing multi-item health measurement rules.
  • the inventor has developed original procedural re-engineering algorithms for four often used rating scales in the evaluation of the efficacy of psychopharmacological drugs, namely the Hamilton Depression Rating Scale (17 items) (HDRS-17), the Montgommery-Asberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), and the Positive and Negative Syndrome Scale (PANSS).
  • HDRS-17 Hamilton Depression Rating Scale
  • MADRS Montgommery-Asberg Depression Rating Scale
  • YMRS Young Mania Rating Scale
  • PANSS Positive and Negative Syndrome Scale
  • the method of the invention relates not particularly to a subgroup analysis, in which a particular subgroup of patients having a specific parameter is further analysed. Instead, the method of the invention relates to re-analyzing the whole set of data of each individual patient in the patient group. Nonetheless, it will be understood that the methods of the invention may be performed on subgroups of the patient group. In addition, the methods of the invention may also be used to diagnose the most possible disorder based on history, symptoms, signs and behaviors.
  • the present invention relates to CNS-related disorders and particularly to mental diseases or disorders which are characterized by an underlying emotion dysregulation.
  • These mental diseases or disorders can be grouped into subclasses as follows: (i) non-cognitive mental disorders comprising mood disorders, anxiety disorders, psychotic disorders, eating disorders, premenstrual syndrome, somatoform disorders , factitious disorders, dissociative disorders, sexual and gender identity disorders, sleep disorders, adjustment disorders, impulse control disorders, pervasive development disorders, attention-deficit disorders, disruptive behavior disorders, substance-related disorders, personality disorders, psychological factors affecting medical conditions, malingering, antisocial behavior, bereavement, occupational problems, identity prob>lem, phase of life problem, academic problem and problems related to abuse or neglect; and (ii) cognitive diseases comprising delirium, Alzheimer Disease, substance-related persisting dementia, vascular dementia, dementia due to HIV disease, dementia due to head trauma, dementia due to Parkinson Disease, dementia due to Huntington Disease, dementia due to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
  • the present invention relates to a method as described herein, wherein said CNS-related disorder is a mood disorder.
  • ICD-10 International Classification of Diseases
  • ICD-10 can be accessed on the internet via: http://www.who.int/classifications/icd/en/.
  • ICD-10 and DSM-IV are specifically hereby incorporated by reference into the present invention.
  • the present invention relates to a method as described herein, wherein the severity of the mood disorder is based on the use of I ists of diagnostic criteria and categories from ICD-10 or DSM-IV.
  • the present invention relates to a method as described herein, wherein said lists of diagnostic criteria and categories from ICD-10 or DSM-IV are organized in an expert system, comprising a database.
  • the present invention relates to a method of evaluating general therapeutic classes into which various psychoadive drugs fall, based on eliminating or diminishing trait symptoms.
  • the method of the present invention may comprise classification tree and random forest supervised classification algorithms to analyze data.
  • multiple statistical methods may be applied to classification and recognition of drug efficacy.
  • Supervised classification analysis methods which can classify patterns of novel data based on prior knowledge of sample classes, include linear discriminant analysis, Fisher discriminant analysis and tree-based analysis.
  • the efficacy of a drug relates to the capacity or power (strength, effectiveness) of said drug to produce a desired effect.
  • Efficacy of the present invention includes a Dose/Response efficacy (e.g. in a study to determine a drug's efficacy), a Long Term efficacy (e.g. in a study to determine a drug's efficacy over a longer period of time than had been studied previously) and New indication efficacy (e.g. in a study to determine a drug's efficacy for an indication other than that for which it is currently approved).
  • Dose/Response efficacy e.g. in a study to determine a drug's efficacy
  • Long Term efficacy e.g. in a study to determine a drug's efficacy over a longer period of time than had been studied previously
  • the present invention thus relates to a method as described herein, wherein said drug efficacy is evaluated as partial response, full response, partial remission or full remission.
  • the invention also relates to a computer program implementing the method, a database, and a navigation system for extracting or visualizing information from the database.
  • One embodiment of the invention is a method and system for assisting with the diagnosis of a patient, wherein history, symptoms, signs and behaviors are selected from a pre-defined selection.
  • the history, symptoms, signs and behaviors may be chosen from a predefined selection set of history, symptoms, signs and behaviors.
  • the predefined selection may be organized alphabetically, according to type of symptoms, according to the history, according to the signs, according to the behavior, etc.
  • a hierarchical selection of symptoms starting with broad grouping is within the scope of the invention. For example, the operator may be presented with a broad group of symptom categories from which subgroups may be selected.
  • the limited choice of symptoms enables the operator to clearly describe the disorder, and also provides more precisely defined terms for searching the database.
  • a similar grouping is possible for history, signs and behaviors.
  • the system of the invention may request further input data, which, may relate also to other patient information such as the sex of patient, age and ethnicity.
  • Such data may be chosen from a predefined list of choices (e.g. sex (M/F), ethnicity (English, Chinese, American, Polish, Indian, Jewish, Asian, South African, Jamaican, etc)).
  • sex M/F
  • ethnicity English, Chinese, American, Polish, Indian, Jewish, Asian, South African, Jamaican, etc
  • Such limited choice enables the operator clearly to define the other aspects of the patient.
  • the categorization of features also provides more clear terms for searching.
  • some input data may be provided as free text description.
  • the input data may also used as input in a database search.
  • the history, symptoms, signs and behavior data are also organized into discrete categories.
  • the categories may be organ ⁇ zed into hierarchical lists. Each top level category may be subdivided into one or more lower level categories.
  • Such discrete categorization provide the database with a robust structu re, particularly suitable for rapid searching and finding associations.
  • the burden of describing the disorder data by the operator of the invention is alleviated. There is no need to use descriptive free text which could otherwise contain subjective terms not recognized by the database or other operators.
  • categorization allows the database to be searched quickly and accurately, since data therein is already structured into the same discrete categories.
  • the use of discrete categories permits the language or definitions of the input choices to be easily switched.
  • the interface with the operator may be selectable to provide choices such as Latin named categories, English named categories, or a set of synonyms associated with a particular branch of medicine. It also enables the output of the categorized conditions to be provided in a different lexicon. Such flexibility permits the invention to operate at different levels of understanding, with experts having different specializations, and in different languages.
  • Another embodiment of the present invention is a database, comprising data regarding disorders already diagnosed and associated with at least one parameter such as one symptom, one sign, a behavioral pattern or the history of a subjed suffering from the disorder.
  • the symptom(s) and other parameters associated with t e disorder are categorized in the database according to a discrete seledion of symptoms possibilities. Hierarchical structuring of the categories is within the scope of the invention, as described above.
  • the database thus comprises a structured organization of pre-diag nosed symptoms, history, signs and behaviors and their associated dis ⁇ ders. It is an aspect of the invention that the discrete categories are expandable or contractible according to new methods of diagnosing, new conditions etc.
  • the database further comprises information in respect of conditions already diagnosed in a subject suffering from the condition.
  • information may be in the form of discrete categories (e.g. sex, race, age) or numerical or textual, non-categorisable information
  • each criterion such as symptom, sign, history and behavior may be assigned a numerical value based on diagnostic DSM-IV criteria, for instance as exemplified in the examples sedion.
  • a further asped of the present invention is an expert system as described herein, wherein the data on symptoms, signs, history, and/or behaviors is provided in a numerical value.
  • Mania Response & Remission System or MRRS may be re-engineered as follows:
  • the present invention relates to a method for evaluating drug efficacy in CNS- related disorders, comprising:
  • the present invention relates to a method for evaluating drug efficacy in
  • re-engineered YMRS comprises:
  • the present invention relates to a method for evaluating drug efficacy in
  • the re-engineered MADRS comprises:
  • the present invention relates to a method for evaluating drug efficacy in CNS-related disorders as described herein, wherein the re-engineered PANSS comprises: all the DSM-IV A-criteria of SCHIZOPHRENIA with: •crit.
  • A1 (DELUSIONS) i1>3 (all) or i5>4 (grandiose) or i6>3 (persecutory) •crit.
  • A2 (HALLUCINATIONS) i3>3 •crit.
  • A3 (DISORGANIZED SPEECH ) i2>3 •crit.
  • A5 (i8>3 or i9>3 or i10>3) (affective flattening) or i13>2 (alogia) or i27>2 (avolition); and the B-criterion and the 'BIZARRE'-condition of the DSM-IV A-criterion of SCHIZOPHRENIA with: • crit.
  • a database of the invention comprises all possible combinations of symptoms and further parameters to which specific attributes and more detailed information are attached. Not all combinations of any two of parameters result in a valid combination - for instance, no data for a particular combination may be known. Means for organising data in databases and database management system are known in the art and any are within the scope of the invention.
  • the parameters in a database is at least 2, and may be 3, 4, 5, 6, 7, 8, 9, 10 or more than 10.
  • the number of parameters can be variable and optimised for all combinations of histories, symptom(s), sign(s), behavior(s) and/or condition(s). When the operator of the invention identifies a symptom, sign and/or behavior, the invention is capable of providing a set of possible disorders.
  • This first step of knowing the symptom(s), signs and/or behavior(s) is similar to the actual working practice of the psychiatrist.
  • the psychiatrist would have to read all available documentation and find out whether there's a matching disorder for each possible symptom, sign and/or behavior. It is not until the information has been read by the psychiatrist that the disorder can be classed. The time spent on reading irrelevant documentation corresponds to lost time.
  • the use of a database of the invention immediately narrows the choices for the operator.
  • the present invention relates to an expert system for evaluating drug efficacy in CNS-related disorders, comprising: (a) a database comprising data of symptoms, signs, history, and/or behaviors and disorders associated therewith, (b) means for inputting data by an operator of symptoms, signs, history, and/or behaviors of individual patients, (c) accessing means to said database, (d) clinimetric rules for setting a diagnosis, (e) rating scale algorithm for setting a diagnosis and (f) means for extracting said diagnosis, whereby the drug efficacy is evaluated.
  • an operator provides the method or system with his choice of symptoms, signs and/or behaviors, and initiates a search of the database, which returns a list of conditions.
  • the search is performed by extracting data from an intersection of the symptoms, signs and/or behaviors crossed by the disorder.
  • the data is extracted along the disorder or condition axis.
  • a further advantage of the database is evident where simultaneous searching is performed of more than one disorder.
  • the search is proceeded by extracting disorder data from intersections of the symptom(s), sign(s) and/or behavior(s) planes crossed by the symptom(s), sign(s) and/or behavior(s) of the disorders.
  • the disorders which are common to the symptom(s), sign(s) and/or behavio ), as well as disorders attributed to the each symptom, sign and behavior are rapidly provided. This feature is helpful in cases of rare conditions that present atypical symptom, sign and/or behavior manifestations, and in which the combination of findings may provide a clue to the correct diagnosis. Using conventional methods, such diagnosis would require extensive cross-referencing of medical literature.
  • the database may provide additional relationships for the sex of patient, age, ethnicity, and the like.
  • the input data permits relationships between for example, ethnicity or age and the likely condition, to be determined.
  • the input data may assist with ranking the diagnoses according to probability. For example, if it is known that there is a predisposition to a type of disorder, such information may be used to increase the probability indication of the disorder.
  • the probability might be presented as a percentage, fraction, or be used to adjust the placing of the condition in an ordered list, for example.
  • the input data may also be used to request further information from the operator. For example, where input data has not been provided by the operator, and the database indicates a relationship between a likely disorder and a further parameter such as age, for example, the system or method may request this information. Such information may be used to change the probability indication of the disorder.
  • the use of further input data significantly improves the speed and accuracy of the diagnosis. The generation of long lists of possible diagnoses is avoided; normally such lists have to be refined by the operator and depends on the knowledge and experience of the operator.
  • the use of predefined input data allows precise questions to be formulated by the invention and provides focused diagnoses.
  • Ranking information is based on the frequency that a particular combination is encountered in practice, for a given combination of symptoms.
  • a default frequency may be provided. Exceptions to this default frequency are explicitly stored, together with the combination of the symptoms for which this exception occurs.
  • the default rankings and exceptions may be defined by experts during the data entry process, based on their own experience and available literature data.
  • An embodiment of the present invention is a database comprising medically defined disorders, wherein at least one dimension is provided for each symptom, sign, behavior and history.
  • the relational links between symptom(s), sign(s), history and/or behavior(s) with disorders are provided in the database, so that the data can be represented and searched across data planes and intersections.
  • Additional information such as age, sex and ethnicity may further influence the ranking of the diagnoses, and may even eliminate some diagnoses from the list.
  • the invention may prompt the operator to enter such relevant information. There from, the probably or ranking of the disease can be established by the invention.
  • the invention allows multiple symptoms to be specified, and may automatically assign a higher ranking to those disorders shared by the given symptom(s), sign(s) and/or behavior(s).
  • diagnosis may also be given a ranking according any correlation between the patient data in respect of age, sex and symptom(s), sign(s) and/or behavior(s), as mentioned above.
  • the database is not updated with continued use by the operator. Instead, the database information is provided only by experts, and is validated.
  • the invention can also be used as a reference medium, comparable to the classical printed or online books.
  • the operator has the possibility to browse the collected information, optionally according to symptom, condition or disorder.
  • the invention may be provided with a search engine, allowing the user to quickly find a particular item of interest, be it a symptom, condition, sign, behavior, disorder, or other content.
  • a further asped of the invention is the use of a discriminative value for the combination of history, symptom(s), sign(s) and/or behavior(s) and disorders.
  • a discriminative value indicates to the method and system whether for the given history, symptom, sign and/or behavior, a history, symptom, sign and/or behavior is discriminative between disorders or is not, respectively.
  • Such value is based on the proven significance of the history, symptom(s), sign(s) and/or behavior(s) in making a diagnosis. If the operator unknowingly identifies a history, symptom(s), sign(s) and/or behavior(s), which has low discriminative value, he might receive the message that this history, symptom(s), sign(s) and/or behavior(s) has a low discriminative value.
  • the invention may then suggest a better approach.
  • the invention may provide a list of diagnoses, in which the discriminative value is used as a factor to order the list by probability.
  • the database may thus comprise the discriminative value as a further feature of the combined history, symptom(s), sign(s) and/or behavior(s) parameter.
  • the discriminative value of a history, symptom(s), sign(s) and/or behavior(s) for a particular disorder may be provided by the expert, and possibly be based on the criteria set out in DSM-IV as mentioned above.
  • a system of the invention may be one or more devices comprising at least one microprocessor capable of performing a method of the invention.
  • the system may comprise at least one or two networked computers.
  • the operator of the invention may be a specialist or a non-specialist in the field of study.
  • An example of an operator of the invention is a psychiatrist or a specialist in for example, psychology, or other practitioner for whom interpretation of symptoms is necessary.
  • the present invention relates to an expert system as described herein, wherein said expert system groups and evaluates data of patient groups.
  • the present invention relates to an expert system as described herein, wherein said expert system groups and evaluates data of a patient group treated with a placebo andOr a patient group treated with a compound to be tested.
  • an operator of the invention identifies the most possible disorder connected with said history, symptom(s), sign(s) and/or behaviors). All possible relevant combinations of history, symptom(s), sign(s) and/or behaviors) and disorders are available in the database. The operator just has to identify and select the appropriate history, symptom(s), sign(s) and/or behaviors). As a result, he is given a focused set of diagnoses Information on the likelihood of each diagnosis for this particular combination of history, symptom(s), sign(s) and/or behavior(s) is also given. For some combinations of history, symptom(s), sign(s) and/or behavior(s), the system may indicate that additional input is required. Input of this additional (patient-related) information by the user results in an optimised ranking of the different disorders for that particular patient.
  • the method or system is integrated within other systems, such as those with which the operator may already be familiar. It is an aspect of the invention that the method, system and/or database has means to be integrated in these applications to which the operator may already be familiar.
  • the method or system is provided with a number of standardized services and interfaces, that will allow the invention to be integrated with other applications.
  • an external application may send a message, containing the request, to the invention implemented as a computer program.
  • the invention may respond with a message containing the result.
  • Such message can be captured by the external application, and processed accordingly.
  • the method is executed using a remote computer.
  • a remote computer Such arrangement permits remote requests to be processed, for example, over the internet, using a network and a central server, or any other remote/central server configuration.
  • the method may be integrated locally by providing a local instance of the content database and corresponding interfaces.
  • the invention is capable of communicating with an operator using speech or sounds.
  • the invention may recognize a vocabulary, and may be able to respond to the user. It may, for instance ask for more input, or provide the results of a particular operation.
  • Such speech integration may incorporate control and output of the operator's usual application, depending on the speech capabilities of this type of application. Such integration would result in a complete speech enabled work flow, so increasing the efficiency of the operator.
  • the vocabulary used in a certain medical area often contains several synonyms and different terminologies, while the data available in a content database often only contains a subset of the available vocabulary.
  • An operator may not be able to understand the terms available for input or provided by an output, or may want to use a more familiar vocabulary.
  • the invention incorporates the use of one or more lexicons.
  • Such lexicons or semantic sources may be built-in or available as "plugs-ins", or as a file of translations, or any other means available to the skilled person. It is an asped of the invention that such lexicon can be expanded by the operator, and/or that an operator can create their own vocabulary, and link it to the application.
  • Such lexicon provides an advantage that search items can be compared with the available lexicons and semantic libraries.
  • the method may then optimise the search criteria, and use the results from this lexical and semantic comparison as input for the search operation, in order to capture all relevant data.
  • the output may also be translated according to the understanding of the operator. This lexical layer integration is particularly useful for the more classical approach of the search engine.
  • the method of the invention may be capable of using data from sources other than the database. If such external resources are available, the invention may be linked to these resources to extend the information.
  • Such external resources include conventional databases and multidimensional databases. It goes without saying that the external sources should be subject to the highest quality criteria. Therefore, a validation of external sources is preferable, and it is even more preferable that external sources are certified. The availability of external sources provides additional flexibility and extensibility to the invention.
  • the invention may thus provide a central integration point for several databases, each built up by a independert providers or partners.
  • Non-interactive formats include the printed form as a book, brochure, or other paper formats.
  • Other examples of non-interactive formats are static electronic information, such as a collection of linked HTML or XML pages, or using other publishing technologies, such as pdf (Portable Document Format).
  • pdf Portable Document Format
  • Interactive formats include the system being integrated in the end user's medical information system such as a EMR (Electronic Medical Record).
  • the operator may interact with the invention using an interface.
  • the interface may be incorporated into a web browser page, a proprietary interface, an interface generated using a database authoring tool etc.
  • the devices providing at least the interface include a mobile phone, a PDA device, an organiser, a desktop computer, a terminal, a networked computer, a system comprising a microprocessor, an input device and a display device.
  • the application of these interactive formats is not limited by the output device.
  • an application may be provided that offers a view to the system.
  • These applications may be further speech enabled.
  • a non-visual, speech enabled application can also be provided as a means to interad with the system.
  • the present invention thus connotes an expert system as described herein, wherein said expert system provides a feedback means to the operator inputting data.
  • Static database content may be installed locally. Provisions of sufficient disk space to store the content database are known to the skilled person.
  • static content may be made available via a web server.
  • Provisions of networking e.g. wired or wireless connection to an intranet or Internet, use of a web browser capable of working with the standard transfer protocols http and https etc) are known to the skilled person.
  • Dynamic, interactive content may be made available by the invention.
  • Such dynamic content may be provided by way of a connedion to the intranet or Internet, and the use of a web browser capable of working with the standard transfer protocols http and https.
  • a method or system is capable of providing an interface for the purpose of browsing data from the database. It may comprise means for extracting data according to the searching requests of the browsing user.
  • the interface may permit graphical one, two or three dimensional representations of data, and means for the browsing user to navigate there through.
  • the system may be capable of providing a primarily textual online book edition of the database as mentioned below.
  • the system may be provided with a search engine allowing the user to specify a number of search criteria.
  • the result set is presented to him, so he can interactively browse any of the results.
  • This engine may be integrated with a Speech Recognition engine to aid the end user in entering the search criteria.
  • the user may be guided by a number of discriminative questions about the problem area which leads to a reduced set of answers, very closely related to the problem.
  • speech recognitbn may help the end user in answering the necessary questions.
  • the present invention relates to a computer program on a computer readable medium capable of performing a method as described herein. Also, the present invention relates to a computer program on a computer readable medium capable of providing functionality of a system as described herein. In a further embodiment, the present invention relates to a computer program on a computer readable medium capable of providing a database comprising data of symptoms, signs, history, and/or behaviors and disorders associated therewith.
  • a database of the invention comprises all possible combinations of histories, symptom(s), sign(s), behaviors) and/or conditions and disorders to which specific attributes and more detailed information may be attached.
  • the content is provided by a group of experts in disorders related to the CNS, that might include, for example psychiatrists, assisted by medical doctors having specialised knowledge about particular disorder. To provide the highest quality, one or more experts from each disorder may provide information to and/or validate the database.
  • an interactive data entry application which guides the data entry operator. Such guidance may be by asking questions to the operator, the use of choice buttons, pull down menus, used such to limit and make consistent the input of the operator. By using such application, the content is entered in a consistent form, and the reuse of pre-existing data is maximized.
  • an interactive data entry application is organized according to the natural work flow, and to the natural relations between the entities in the database.
  • the data entry operator identifies the location, optionally sub location, pattern, disease, or a combination thereof.
  • the data entry user may add characteristic information towards any type of entity encountered. This characteristic information is divided into several categories, which further enhances the search capabilities of the invention.
  • the charaderistic information can consist of short descriptions, long descriptions, figures, with or without captions. Additionally, references to official publications, if applicable, are stored together with the corresponding data. According to an asped of the invention, the categories are configurable. If, at a certain moment, the operator is required to provide an additional characteristic, such characteristic may be added to the system.
  • the data entry application may be speech enabled. Additional interfaces may be provided for import of data in several structured formats (e.g. comma separated text, spreadsheets, XML documents). This interface may extend the solution to also input third party data or data from remote data entry users.
  • structured formats e.g. comma separated text, spreadsheets, XML documents.
  • Validation and Approval It is an aspect of the invention the system is configured to prevent data being published, either interactively or non-interactively, without specific approval of dedicated Validation users and Approvers. Validation users and Approvers may be different from the data entry users who are responsible for entering the bulk of the data into the database.
  • Such configuration may allow every data item to be checked before it is released as publishable data.
  • the user responsible for validation and/or approval of the data may be presented a list of non-validated modifications.
  • Navigation system One aspect of the invention is a system for navigating a medical database as mentioned herein.
  • the system comprises a means for accessing a database, a means for inputting navigational information, and means for extracting from the database a list of conditions, history, symptom, sign, behavior and disorders, depending on the navigatbnal information.
  • the system may provide navigation tools including interactive displays which make use of alphanumerical characters and graphics to represent the data.
  • the information contained within the system can be browsed along several axes, depending on the known input parameters. The most natural work flow is to provide input about the history, symptom, sign, behavior and/or condition, but the system will also allow to be browsed as an encyclopaedia for information related to history, symptom, sign, behavior and conditions in case the disorder is known.
  • a navigation system comprises means to providing results of navigation as one or more of text, numbers, case examples, drawings, computer generated graphics, video clips, or any other type of relevant output.
  • the methods or systems of the invention may be provided as a computer program held on a computer readable medium, said program comprising computer code for performing the steps of the method or for providing the fundionality of the system. Examples of media include an optical disk, tape, magnetic disk, solid-state memory, hard-drive.
  • the program or system may be available for download across a network.
  • a method or system is implemented into a stand-alone system, for example, as a package on a desktop computer with a screen and input device, on a laptop computer, on a PDA etc.
  • One embodiment of the invention is a device capable of performing a method of the invention.
  • the database may be present on a remote server and a program present on a networked local computer to provide an operator with an interface for interading with the database.
  • Such interface may by provided by known technologies, for example, displayed in a web page, a proprietary interface, an interface generated using an authoring tool etc.
  • the invention includes any technology which permits the operator to interact with the invention.
  • the invention is capable of displaying a web page on a remote computer. Said web page permits the operator to use the invention. It is an aspect of the invention that the use of the method or system by the operator is recorded by the invention for the purpose of billing the operator or his employer. Such billing systems are known in the art.
  • the invention may provide each operator with an account which is charged according to the use of the invention. Such charging may be according to time, the number of searches, complexity of searched, volume of data transfer, or by license with privilege options, etc.
  • the database is preferably curated by a team of experts in history, symptom(s), sign(s), behavior(s) and/or conditions recognition.
  • the database comprises at least two parameters, with history, symptom(s), sign(s), condition(s) and/or behavior(s) vis a vis disorders data. Further input data comprising the sex of patient, age, ethnicity, and psychological antecedents, for example, may be provided in additional parameters.
  • the database comprises all possible combinations of history, symptom(s), sign(s), behavior(s) and/or conditions and disorders to which specific attributes and more detailed information are attached.
  • a database produd is capable of providing or interacting with an interface for the purpose of browsing data from the database.
  • the interface may comprise means for extrading data according to the searching requests of the browsing user.
  • the interface may permit graphical one, two or three dimensional representations of data, and means for the browsing user to navigate there through.
  • the database may be capable of providing a primarily textual online book edition of the database as mentioned below.
  • the database produd may be provided with a search engine allowing the user to specify a number of search criteria.
  • the result set is presented to him, so he can interactively browse any of the results.
  • This engine may be integrated with a Speech Recognition engine to aid the end user in entering the search criteria.
  • the database user may be guided by a number of discriminative questions about the problem area which leads to a reduced set of answers, very closely related to the problem. Again, speech recognition may help the end user in answering the necessary questions.
  • One embodiment of the invention is a device comprising the database product or capable of accessing the database product.
  • the database product may be provided as a computer program held on a computer readable medium. Examples of media include an optical disk, tape, magnetic disk, solid-state memory, hard-drive.
  • the database program or system may be available for download across a network. It may be available under licenseor pay-per-use.
  • the present invention closely follows the natural work flow of the psychiatrist or medical specialist. Contrary to the current state-of-the-art, the invention allows a considerable reduction in the need for manual intervention, by making an automatic pre-selection based on a number of well-known measurable parameters. As such, the invention facilitates and improves psychiatrist work flow, i.e. the extraction of relevant information from symptoms.
  • the invention is structured around a relationship between symptom(s), condition(s) and disorder(s), and shows further dimensions according to case specific parameters such as age, sex, etc. This allows a business intelligence like approach to a content database.
  • the introduction of a ranking of symptom(s) and condrtion(s) for a particular set of input parameters helps to objectify and thus to increase the quality of the diagnoses, for instance by eliminating and/or reducing trait symptoms.
  • the present invention helps to objectify and increase the assessment of clinical trials of compounds by eliminating and/or reducing trait symptoms. It will be understood by the person skilled in the art that the present invention assists in studies of the incidence and distribution of a disorder in a population, and the use thereof to find the causes, modes of transmission, and methods for control of disease (e.g. in epidemiologist).
  • the invention enables the user to obtain relevant information after having identified some basic parameters such as symptom(s) and condition(s).
  • the invention covers process that enables the transformation of symptom(s), sign(s), history, behavior(s) and condition(s) to diagnoses, and the technical structure of the system is irrelevant to the operator.
  • Figure 1A Efficacy on week 8 of test compound X in MDD (MADRS).
  • Figure 1C MADRS total score at baseline.
  • Figure 1 D Difference of MADRS total score at week 8.
  • Figure 1E MADRS total score at week 8.
  • Figure 1 F Remission (MADRS total score at baseline ⁇ 10)(%) at week 8.
  • Figure 1G Qualitative partial remission (%) at week 8.
  • Figure 2 Screen print showing interface produced by a customized application of the NECT built up via decision trees.
  • Figure 3 Screen print showing interface produced by a customized application of the NECT built up via decision trees.
  • Figure 4 Screen print showing interface produced by a customized application of the NECT built up via decision trees.
  • EXAMPLE 1 Re-engineering of the Young Mania Rating Scale (YMRS).
  • MRRS Mania Response & Remission System
  • EXAMPLE 2 Re-engineering of the Study 'Double-Blind Flexible Dose Comparison of the Efficacy and Safety of a test compound and Placebo in the Treatment of Major Depressive Disorder'
  • DRRS Dep ression Response & Remission System
  • This re-engineering is based on the fact that all the diagnostic DSM-IV A-criteria and the B- criterion of the Major Depressive Episode (MDE) can be ruled out by converting the scores on the HDRS-17 or the MADRS items, namely for the HDRS-17:
  • MILD MDE 5 or 6 A-criteria and no disability with unusual effort (UE) or mild disability (MD)
  • MODERATE MDE - 5 or 6 A-criteria and clear-cut, observable disability (DIS) - or 7 or more A-criteria and no disability with unusual effort or mild disability
  • SEVERE MDE 7 or more A-criteria and clear-cut, observable disabil ⁇ ty
  • Figure 1B provides MADRS: baseline distribution.
  • Figure 1 C provides MADRS total score at baseline.
  • Figure 1D provides the difference MADRS total score at week 8.
  • Figure 1E provides MADRS total score at week 8.
  • Figure 1 F provides remission (MADRS total score at baseline ⁇ 10)(%) at week 8.
  • Figure 1G provides the qualitative partial remission (%) at week 8.
  • EXAMPLE 3 Re-engineering of the Positive And Negative Syndrome Scale (PANSS).
  • SRRS Schizophrenia Response & Remission System
  • A5 (i ⁇ >3 or i9>3 or i10>3) (affective flattening) or i13>2 (alogia) or i27>2 (avolition) 2)
  • the B-criterion and the 'BIZARRE'-condition of the DSM-IV A-criterion of SCHIZOPHRENIA can be ruled out via the PANSS namely: • crit.
  • NECT Neuronal Electronic Clinical Trial
  • the inventor developed an electronic data capturing system via electronic item-windows grouped in relevant clinical decision tables, intelligently presented via forward and backward chaining techniques which leads to a semi - mandatory data collection and a real time data control and explanation.
  • the inserted electronic data analysis gives via item related computer algorithms in real time an objective fulfilling of all the, in the clinical trial defined, clinical criteria and measurements.
  • MADRS TOTAL SCORE 25.8 27.9 25.0 31.0 25.7 29.0 26.6 31.6

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Abstract

L'invention porte sur le diagnostic automatique de patients et sur des essais cliniques. Elle concerne plus particulièrement l'utilisation d'algorithmes cliniques mis au point de manière originale au moyen d'un système logiciel expert afin d'exprimer les diagnostics de patients atteints de maladies liées au système nerveux central (SNC), et pour la mise en oeuvre et l'analyse d'essais cliniques dans le domaine du SNC. Cette invention se rapporte à un procédé d'évaluation de l'efficacité de médicaments pour des maladies associées au système nerveux central, des symptômes de caractère étant éliminés. L'invention porte aussi sur un système expert et sur des programmes informatiques de mise en oeuvre de ce procédé.
PCT/EP2005/003682 2004-04-07 2005-04-07 Utilisation d'algorithmes cliniques actionnes par un systeme expert dans des essais cliniques du systeme nerveux central WO2005098725A2 (fr)

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WO2014105752A1 (fr) * 2012-12-28 2014-07-03 Revon Systems, Llc Systèmes et procédés d'utilisation de dossiers médicaux électroniques conjointement avec des applications de patients
CN110197723A (zh) * 2019-07-03 2019-09-03 四川大学华西医院 心身医学理论框架下的临床躯体症状分类诊断系统

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014105752A1 (fr) * 2012-12-28 2014-07-03 Revon Systems, Llc Systèmes et procédés d'utilisation de dossiers médicaux électroniques conjointement avec des applications de patients
CN110197723A (zh) * 2019-07-03 2019-09-03 四川大学华西医院 心身医学理论框架下的临床躯体症状分类诊断系统

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