FR3110379A1 - Methods for identifying subjects potentially contaminated by a pathogen, and method, system and software for monitoring the contamination of a population - Google Patents

Abstract

The invention relates to the identification of subjects potentially contaminated with a pathogenic agent. A method (100) of identification comprises determining (102) at least one first variable (V) by measuring (101), on a first sample (21) of a bodily fluid from a subject, at least one quantity indicative of contamination of the subject by a pathogenic agent. The first variable (V) is compared with a first threshold (T1) and a second threshold (T2) strictly greater than the first threshold (T1), the first threshold (T1) and the second threshold (T2) defining an interval of potential contamination . The subject is identified as potentially contaminated (107) by the pathogenic agent if the first variable is included in the interval of potential contamination, and as contaminated (106) or as not contaminated (104) otherwise. For subjects identified as potentially contaminated, contamination or non-contamination can be confirmed by comparing a rate of change (R) of an indicative quantity, of the first variable or of an additional variable with a threshold value (R1). Figure for the abstract: Fig. 3

Description

Methods for identifying subjects potentially contaminated with a pathogenic agent, and method, system and software for monitoring the contamination of a population

The invention relates to the field of the identification of subjects contaminated or potentially contaminated by a pathogenic agent, and to the field of monitoring the contamination by a pathogenic agent of a population.

The term "pathogenic agent" means any biological agent capable of causing the disease, such as a virus, a bacterium, or a protozoan, for example. By “subject” is meant a human being or possibly another living organism likely to be contaminated by a pathogenic agent, and by “population” a plurality of subjects.

“Contaminated” and its derivatives designate the fact that the pathogenic agent is present in the body of the subject, without necessarily causing the disease associated with the pathogenic agent. Contamination is thus distinguished from infection, where the subject is contaminated with the pathogenic agent and additionally affected by the disease associated with the pathogenic agent. It is also recalled that a subject who is contaminated but asymptomatic, that is to say not showing any symptoms, or paucisymptomatic, that is to say showing few symptoms, can be contagious in the same way as a subject infected. The same applies to a subject in the incubation phase of the disease.

Technology background

The tools currently used for screening for contamination by a pathogenic agent are tools intended for diagnosis, based on the principle of the greatest possible certainty of contamination or non-contamination of the subject tested, or optimization of predictive values. They do not take into account the importance of adopting more effective methodologies and strategies to carry out a more efficient statistical sorting, and especially earlier to detect people likely to be contaminated as soon as possible, even though the values predictive data cannot yet be optimal, in order to prevent them from contaminating the population.

Indeed, in the early phase, when using biomarkers that have not yet had time to evolve significantly, a contaminated person will be detected as not contaminated by such tools, and will be able to freely contaminate those around them, who will contaminate in turn its own surroundings, with the effect that the disease caused by the pathogen increases exponentially in the population.

To make a diagnosis, there are generally two main types of information sources: on the one hand the reference examinations, also called the "gold standard" in English, which give a binary response of the sick/non-sick type and that are 100% sure; and on the other hand the diagnostic tests, which are generally imperfect and constitute an aid to the diagnosis, while not necessarily being 100% reliable.

A diagnostic test may not be reliable in terms of identifying sick subjects (this is called a "false negative", i.e. the test concludes with negativity when the subject is affected), and /or in terms of identification of non-sick subjects (we then speak of “false positive”, ie the test concludes with positivity when the subject is healthy).

Among the diagnostic tests, there are mainly three types: binary response tests giving a “positive/negative” type response, ordinal response tests giving a “high probability”, “intermediate” or “weak” type response, and quantitative tests providing continuous or discrete value.

Usually, these diagnostic tests are tested against clinical certainties concerning the person's pathology and/or against reference examinations or "gold standards" which are 100% reliable.

In order to know the performance of a diagnostic test, a population is studied and a contingency table, such as table 1 below, is constructed:

Sick Not sick Number Positive test true positive False positive nT+ Negative test False negative true negative nT- Number nM+ nM- nTOT

where nM+ is the number of sick subjects within the population considered, nM- the number of non-sick people, nT+ the number of people having been identified positive to the test, and nT- the number having been identified negative. We also have nM+ + nM- = nT+ + nT- = nTOT.

The sensitivity of a test is defined, on a studied population, as the ratio Se given by equation 1 below:

where VP is the number of true positives and FN is the number of false negatives on a given population of true patients whose status is confirmed on the basis of a gold standard test and/or medical examinations . The denominator VP+FN is then the total number of confirmed patients. Se is between 0 and 1. We have Se = 1 when there are no false negatives (i.e. FN = 0): the negative predictive value, which represents the ability to discriminate between true negatives from false negatives, is then optimal, but even in this case, there can be false positives. If Se=1, the test is very sensitive, and makes it possible to exclude the disease for sure when it is negative.

The specificity of a test is defined, on a studied population, as the ratio Sp given by equation 2 below:

where VN is the number of true negatives and FP the number of false positives in a given population of people who are not sick and whose status is confirmed on the basis of a gold standard test and/or d 'medical exams. The denominator VN + FP is then the total number of confirmed non-patients. Sp is between 0 and 1. We have Sp = 1 when there are no false positives (i.e. FP = 0): the positive predictive value, which represents the ability to discriminate between true positives from false positives, is then optimal, but even in this case, there can be false negatives. If Sp = 1, the test is very specific, and confirms the disease for sure when it is positive.

The likelihood ratio L is given by equation 3 below:

where Se and Sp have the definitions given above. L is between +1 and +∞. When a diagnostic test manufacturer develops a new test, it seeks to maximize L, which requires minimizing both the number of false negatives FN and the number of false positives FP, to achieve optimization of predictive values.

When a diagnostic test provides a quantitative value, the ideal case is when the test is discriminating. Such a case is illustrated in the graph represented in FIG. 1, where the T values that can be indicated by the test have been plotted on the abscissa, and the number N of subjects presenting this test value on the ordinate, and where the curve CM obtained for the sick subjects on the one hand, and the CH curve for the non-sick subjects on the other hand. The CM and CH curves are disjoint, and consequently, there is no possible error: it suffices to choose a threshold S, materialized by the dotted line, between the two curves, and the diagnostic test is almost reliable at 100%: in other words, the test provides ideal sensitivity Se and specificity Sp, i.e. not very different from 1.

However, as shown in Figure 2, it may be that the CM and CH curves corresponding to sick subjects and non-sick subjects overlap, that is to say that for certain T values of the test, the subject may be either sick or not sick. This case will frequently occur for newly created diagnostic tests to detect people infected in the context of a new pandemic, a fortiori when trying to detect people infected early, when the biomarkers selected for such diagnostic tests have still little evolved and that the state of the subject, from the point of view of its physiological parameters, in particular blood, will still be close to the healthy state. When the CM and CH curves overlap, moving the threshold S, materialized by the dotted line, inevitably involves increasing the number of false negatives (materialized by the hatching FN) and therefore decreasing the sensitivity Se, or else increasing the number of false positives (shown by the FP hatching) and therefore to reduce the Sp specificity. In such a case, the threshold S selected inevitably constitutes a compromise between the Se sensitivity and the Sp specificity.

The coronavirus disease 2019 (Covid-19 or COVID-19) pandemic challenges the above concepts in several ways. During the first months of this pandemic, there was in fact no method to clinically define with certainty whether a sick subject is really suffering from Covid-19 or from another pathology, and it is logical to suppose that the the same situation may recur in possible future pandemics. Nor did there exist during the first months of this pandemic a reference test (“gold standard”) allowing the identification with certainty of subjects suffering from Covid-19. Even one of the most reliable tests and currently the most used on a large scale, the identification of SARS-CoV-2 by polymerase chain reaction (PCR), would only present according to studies a reliability of only 40% to 70%, depending on the tests carried out. It is specified here that it is not a question of the reliability of the only identification of SARS-CoV-2 by PCR, which is optimal, but of the overall reliability of the test including a sample collection phase followed identification of SARS-CoV-2 by PCR. In such a context, the use of the usual methodologies for the development of diagnostic tests becomes complex, even haphazard and inefficient. For example, in the absence of reliable references, it is difficult to quantify the false negative rate of a new diagnostic test, since the methods for identifying SARS-CoV-2 by PCR may also pass. next to the determination of positivity of number of subjects. Similarly, given the high rate of asymptomatic or paucisymptomatic carriers, the quantification of the false positive rate of a diagnostic test is also subject to caution, since the subjects tested positive are perhaps really contaminated but without symptoms and not detected by the methods of identification of SARS-CoV-2 by PCR, therefore wrongly considered as healthy.

The difficulty is further increased by an additional problem: the need to detect contamination as early as possible, in order to isolate the people affected and prevent them from contaminating those around them. This need is critical among the nursing staff, subject to a high risk of contamination by the patients and likely to transmit the contamination to a large number of other patients (what is referred to as "super-diffusers"). ). However, the more one seeks to detect a contaminated person at an early stage, the more one seeks to qualify a weak measurement as positive, in other words the more one lowers the detection threshold. As explained above, this inevitably considerably increases the rate of false positives, even though it is impossible to quantify this rate with precision for lack of a reliable reference test: the specificity is then greatly degraded.

The diagnostic tests developed in an emergency have thus been the subject of choices of thresholds carried out in an emergency but whose optimization raises questions, and for which many unknowns remain.

There is therefore a particularly pressing need for methods allowing more efficient and earlier identification of subjects infected with SARS-CoV-2, which causes Covid-19. Indeed, since most subjects infected with SARS-CoV-2 do not show symptoms, or only show symptoms that are difficult to distinguish from milder illnesses, the only identification of subjects with symptoms followed by their isolation is insufficient to stem the Covid-19 pandemic. Moreover, due to the rather long incubation time of the disease, estimated at 6 or 7 days but which can reach 12 days, the isolation of people at the time of the symptoms does not prevent them from having potentially contaminated their entourage for several days, and we immediately understand that the early detection and the effectiveness of the screening of people who may have been contaminated are key factors in stopping the exponential spread of such a contagious disease. In addition, it has been shown that earlier management of patients, including their medication, can reduce the severity of the disease, which also accentuates the importance of early detection.

A number of methods for identifying subjects infected with SARS-CoV-2 have been proposed to date.

Among these methods, mention may be made of the methods for identifying SARS-CoV-2 by polymerase chain reaction (PCR), already mentioned above, and the methods for identifying SARS-CoV -2 from saliva or mucus samples obtained by nasal, pharyngeal or oral swab.

However, PCR methods have various disadvantages: in addition to the fact that they are not available in the necessary quantities, they are time-consuming to implement and are not economical enough to systematically test a large population. They are also not sufficiently reliable since a large percentage of false positives is observed, probably due to the nasal or oral sampling method.

Methods relying on nasal, pharyngeal or buccal swabs, on the other hand, regardless of their possible slowness and high cost, depend greatly on the chance of catching a sample that does contain SARS-CoV-2 at the time of sampling. . In addition, the actual presence of SARS-CoV-2 in the nose or throat may depend on what the test subject did just before (sneezed, coughed, swallowed, drank, etc.) as well as on the phases of the disease. It has thus been estimated by certain studies that they have a false negative rate of 30% to 40%, that is to say that 30% to 40% of the subjects tested who are actually contaminated with SARS-CoV- 2 are incorrectly identified as not being contaminated. Some of these methods such as PCR are specific, i.e. they have a low rate of false positives, and Sp is close to 1, but the sensitivity Se is poor: such a high rate of false negatives is unsuitable for screening, the method being supposed to be applied to a large population in order to allow the necessary measures to be taken to stem the Covid-19 pandemic. Too many contaminated subjects would not be identified as contaminated when they should be. In addition, the person in charge of taking such a sample runs the risk of being contaminated himself by a possible sneeze, cough or particles of the subject to be tested. Finally, the quantity and reproducibility of the measurements is doubtful, due to the vagaries of the samples.

In addition, the screening or diagnostic methods proposed hitherto have generally been based on a display of the “contaminated/uncontaminated” type, which may appear in the form of the coloring of a strip of a test. qualitative or a display on a screen according to a quantitative measurement and its comparison with a pre-established criterion or threshold of positivity.

The sensitivity of such binary methods has so far proved to be insufficient and the detection of contamination too late to allow quarantine of infected people before they infect other people.

Methods of the type based on a quantitative measurement perform a measurement of a quantity indicative of the contamination of the subject by SARS-CoV-2, and a comparison of this indicative quantity with a single threshold. As explained previously, the threshold is set empirically by the designer of the method in an attempt to minimize both the false negative rate and the false positive rate. However, by excessively minimizing the rate of false positives, we run the risk of not detecting subjects infected with SARS-CoV-2 until too late and therefore of not being able to take the necessary quarantine measures early enough to avoid infection. contamination of the professional or family environment, and if necessary the clientele or meetings of the screened subject, and thereby stem the progression of the Covid-19 pandemic.

In view of the above, it would be particularly advantageous to be able to have methods making it possible to screen and identify subjects infected with SARS-CoV-2 with improved sensitivity and precocity. It would be even more advantageous if these methods could be applied to different test techniques and to a large number of subjects, quickly and at low cost. Be able to distinguish a person who naturally has a measurement that is little different from that of a healthy person during the test (either because they have a slightly higher basal level or because the measurement has an error or noise) d a person at the beginning of the contamination cycle would be of strategic importance; however, the way in which current diagnostic tests are used does not allow this.

Summary

One idea underlying the invention is to replace the single threshold value of the methods discussed above with two predetermined thresholds, one being greater than the other, and thus creating an interval which we will call "potential contamination". ". The subject is identified as potentially contaminated if a variable obtained from at least one quantity indicative of its contamination is between these two predetermined thresholds, that is to say in the interval of potential contamination, as contaminated if the variable is on one side of the potential contamination interval, and as uncontaminated if the variable is on the other side of the potential contamination interval. This use of two predetermined thresholds instead of one threshold improves the sensitivity of the method as will be detailed later.

According to one embodiment, the invention provides a method for identifying subjects potentially contaminated with a pathogenic agent, the method comprising:
- determining at least one first variable by measuring, on a first sample of a bodily fluid from a subject, at least one quantity indicative of contamination of the subject by a pathogenic agent;
- comparing the first variable with a first threshold and a second threshold strictly greater than the first threshold, and
- identify:
a) the subject as contaminated by the pathogenic agent if the first variable is one of strictly greater than the second threshold and of strictly less than the first threshold;
b) the subject as potentially contaminated by the pathogenic agent if the first variable is between the first threshold and the second threshold;
c) the subject as not contaminated by the pathogenic agent if the first variable is the other of strictly greater than the second threshold and of strictly less than the first threshold.

“Body fluid” means any liquid or substantially liquid substance produced by the body of the subject. Equivalently, a bodily fluid can be referred to as “biological fluid” or “bodily fluid”. Examples of bodily fluid are, without limitation, urine, blood, lymph, saliva, nasal mucus, sweat. Thus, the first sample can then be taken from the subject by known sampling methods. The first sample can be taken immediately before the implementation of the method, but alternatively it can also be collected and stored for a later implementation of the method. The first sample is not intended to be reintroduced into the subject's body after the implementation of the method.

The term "quantity indicative of contamination of the subject by a pathogenic agent" means any quantity which is measurable and which either indicates in itself a contamination of the subject, or else indicates a physiological consequence of this contamination.

The first variable can be the quantity itself, a quantity calculated according to a single quantity, or a quantity calculated according to several quantities.

With this method, the first threshold plays the role of a threshold allowing the detection of potential contamination, and the second threshold plays the role of a positivity threshold allowing confirmation of the actual contamination of the subject, or vice versa. Subjects located below or above these two thresholds are immediately identified as not contaminated or contaminated, which makes it possible to avoid taking new samples from these subjects, and, for subjects identified as contaminated, to take immediately take the necessary measures to prevent them from infecting other people, in particular quarantining themselves and those around them. Subjects falling between these two thresholds, i.e. within the range of potential contamination, are identified as potentially contaminated. They can then be immediately subject to temporary quarantine for a relatively short period, for example for one to three days, until their actual contamination is confirmed, either by a medical examination and/or another diagnostic method. , or by taking an additional sample as will be detailed later in connection with one of the embodiments of the method. During this temporary quarantine of the subject, temporary quarantine and/or screening of persons with whom the subject has been in contact may be undertaken, without waiting for confirmation of the subject's contamination. In the case of a highly contagious disease such as Covid-19, such immediate temporary quarantine accompanied by temporary quarantine and/or screening of people with whom the subject has been in contact can make all the difference for the people with whom the subject has been in contact as well as for the community.

It is understood that by retaining two thresholds instead of just one and by identifying as potentially contaminated the subjects lying between these two thresholds, the sensitivity of the method is improved compared to a method using a single threshold, even if it means identifying at mistakenly certain subjects as potentially contaminated at first. In other words, the method makes the choice, by retaining these two thresholds, to favor first a good sensitivity by initially accepting a degraded or mediocre specificity, the specificity being able to then be improved either thanks to a medical examination and/or another diagnostic method, or by taking an additional sample as will be detailed later in connection with one of the embodiments of the method. It is specified here that the fact of identifying a subject as potentially contaminated consists only in identifying as "doubtful" the case of this subject, his actual contamination having to be confirmed, and not in concluding that the subject is contaminated or not contaminated. .

It should be noted that the threshold which plays the role of a positivity threshold making it possible to confirm the real contamination of the subject can either be set equal to the threshold of an already existing diagnostic test or according to the usual methods for determining such thresholds, or be set at a more selective value in order to improve the specificity of the method, that is to say in order to rule out more false positives among the subjects identified as contaminated by the comparison with this threshold.

It should also be noted that the first threshold and/or the second threshold can be adjusted according to the evolution of the epidemic or the pandemic that one seeks to stem using the large-scale method. For example, if many devices for implementing the method are available, and the budgets allow them to be acquired in large numbers, the threshold allowing the detection of potential contamination can be adjusted in order to increase the number of subjects. identified as potentially contaminated. Conversely, if the budgets are limited, if the number of devices is insufficient, or if the number of devices allowing a possible confirmation is insufficient, all these cases being able to occur in a pandemic period, then the threshold allowing the detection of a potential contamination can be adjusted in order to limit to the most probable cases of contamination the number of subjects requiring the use of another diagnostic method or the taking of an additional sample, the objective then being to remain able to confirm the possible contamination of all subjects identified as potentially contaminated, without affecting the total number of subjects who can be screened.

It should also be noted that the method does not consist in the diagnosis of the disease caused by the pathogenic agent from its symptoms, but in the identification of subjects contaminated or potentially contaminated by the pathogenic agent from at least one indicative quantity. With the exception of the sample, which can sometimes require a certain level of training, it therefore requires neither the intervention of a doctor nor the presence of the subject at the time of identification, and it can even be carried out on a device. capable of performing required measurements on bodily fluid samples and providing identification. It can therefore be applied to a large number of subjects by unskilled personnel, as long as enough such devices are available. Consequently, in the context of a new pandemic, even if high-performance laboratory serological tests were developed, the method would retain the interest of being able to be implemented to carry out massive screenings and/or to regularly test a population. whole or certain categories of the population.

According to embodiments, such a method may comprise one or more of the following characteristics.

According to one embodiment, the first threshold and/or the second threshold are determined as a function of at least one characteristic of the subject.

By “characteristic of the subject”, is meant any quantity or information capable of characterizing the physiology of the subject. Examples of such characteristics are, without limitation, the age, sex or weight of the subject or the presence of other pathologies (co-morbidities in the event of contamination).

Thus, the first threshold and/or the second threshold can be adapted to the physiology of the subject, possibly on the basis of experience. This improves the performance of the method.

According to one embodiment,
- or the first variable is a variable likely to increase during a period of time following the contamination of the subject by the pathogenic agent, and the subject is identified as:
a) contaminated by the pathogenic agent if the first variable is strictly greater than the second threshold;
b) potentially contaminated by the pathogenic agent if the first variable is between the first predetermined threshold and the second threshold;
c) not contaminated by the pathogenic agent if the first variable is strictly lower than the first threshold;
- or the first variable is a variable likely to decrease during a period of time following the contamination of the subject by the pathogenic agent, and the subject is identified as:
a) contaminated by the pathogenic agent if the first variable is strictly lower than the first threshold;
b) potentially contaminated by the pathogenic agent if the first variable is between the first threshold and the second threshold;
c) not contaminated by the pathogenic agent if the first variable is strictly greater than the second threshold.

It is understood that the method can thus be used both for variables which would increase according to the evolution of the disease and for variables which would decrease according to the evolution of the disease, the roles of the first and of the second threshold being simply reversed in the latter case.

According to one embodiment,
- a plurality of first variables are determined by measuring, on the first sample, a plurality of quantities indicative of contamination of the subject by a pathogenic agent;
- each of the first variables is compared with a first threshold and a second threshold strictly greater than the first threshold or a single threshold, and
- the subject is identified:
a′) as being in the recovery or immunity phase if the measured values of at least two indicative quantities meet a recovery or immunity criterion;
b′) failing this, as contaminated by the pathogenic agent if at least one of the first variables is strictly greater than or strictly less than one of the corresponding first threshold and of the corresponding second threshold or of the single corresponding threshold;
c′) failing that, as potentially contaminated by the pathogenic agent if at least one of the first variables is between the corresponding first threshold and second threshold;
d') as uncontaminated by the pathogen otherwise.

Thus, several variables constructed from several quantities indicative of the contamination of the subject are used simultaneously for the identification of the subject; if the comparison of at least one of these variables with the corresponding threshold or thresholds leads to the identification of the subject as contaminated, the confirmation of this contamination by a medical examination and/or by another diagnostic method is no longer necessary. This improves the performance of the method.

Alternatively, the criterion of cure or immunity can be omitted, i.e. the subject is only identified as contaminated, potentially contaminated or not contaminated by the criteria b'), c') and d'). .

According to one embodiment, one of the first and of the second threshold allows detection of the contamination by comparison of the first variable with said threshold with a false positive rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%, and the other of the first and of the second threshold allows detection of non-contamination by comparison of the first variable with said threshold with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%.

Par “allows detection of contamination by comparison of the first variable with said threshold with a false positive rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2 %, 1% or 0.1%", it is meant that if the subjects of a group of subjects were identified as contaminated or non-contaminated only by comparing the first variable with the said threshold, the subjects identified as contaminated on would be with a false positive rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%. Par “allows detection of non-contamination by comparison of the first variable with said threshold with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5% , 2%, 1% or 0.1%", it is meant that if the subjects of a group of subjects were identified as contaminated or non-contaminated only by comparison of the first variable with said threshold, the subjects identified as non-contaminated would be with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%.

According to one embodiment, one of the first and of the second threshold is determined so as to optimize a negative predictive value and a positive predictive value associated with detection of the contamination by comparison of the first variable with said threshold, and the other of the first and second threshold allows detection of non-contamination by comparison of the first variable with said threshold with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%.

By “negative predictive value” we mean the ability to discriminate between true negatives and false negatives. By “positive predictive value” we mean the ability to discriminate between true positives and false positives. Par “allows detection of non-contamination by comparison of the first variable with said threshold with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5% , 2%, 1% or 0.1%", it is meant that if the subjects of a group of subjects were identified as contaminated or non-contaminated only by comparison of the first variable with said threshold, the subjects identified as non-contaminated would be with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%.

According to one embodiment, the first threshold is between 0.05 times and 0.9 times the second threshold, preferably between 0.2 and 0.5 times the second threshold, more preferably between 0.3 and 0.4 times the second threshold.

According to one embodiment, if said subject has been identified as potentially contaminated with the pathogenic agent, the method further comprises:
- measuring, on an additional sample of said bodily fluid of said subject taken at a time interval t after the first sample, at least one indicative quantity;
- determining a rate of change over the time interval t of an indicative quantity, of the first variable or of an additional variable, and
- identifying the subject as contaminated or not contaminated by the pathogenic agent at least according to a comparison between the rate of change and a threshold value.

Like the first sample, the additional sample can be taken from the subject by known sampling methods, and is not intended to be reintroduced into the body of the subject after the implementation of the method.

The term “rate of change over the time interval t” is understood to mean a quantity which is representative of a temporal evolution of the quantity or variable considered during the time interval t, that is to say between the samplings of the first sample and additional sample. The rate of change can be a dimensionless quantity as well as a dimensioned quantity The rate of change can thus be a dimensionless percentage of evolution, a percentage of evolution per unit of time, a variation of a quantity, or a variation of one magnitude per unit time.

As mentioned above, the fact of identifying as potentially contaminated the subjects lying between the two thresholds for at least one of the variables improves the sensitivity of the method compared to a method using a single threshold, even to wrongly identify certain subjects as potentially contaminated at first. For these subjects, the rate of change over the time interval t helps distinguish false positives from true positives. Indeed, in the initial phase of the disease, from the moment when the at least one indicative quantity becomes detectable, its evolution can be rapid, typically of the order of 10% to 100% per day, which allows, for a second measurement on the additional sample, to identify the subject as not contaminated, thereby eliminating false positives.

Thus, the method not only exhibits good sensitivity through the two cutoffs as discussed above, but also good specificity through the use of the additional sample. It is therefore much more efficient than the classic methods discussed above based on the search for a compromise between sensitivity and specificity.

The time interval t can be relatively short, for example comprised between 12 hours and 72 hours, preferably comprised between 24 hours and 48 hours, so that the period is both short enough not to isolate a person who would turn out to be uncontaminated, and long enough for the evolution of the indicative quantity to exceed the "background noise" of the analysis technique. It is thus possible to confirm relatively quickly the contamination or the non-contamination of the subject. Indeed, certain indicative quantities, such as the quantity of IgM or IgG immunoglobulins, can have growth rates of the order of +20% to +50% per day, which can greatly exceed the " background noise” of the analysis technique.

It should also be noted that the fact of comparing the rate of change to a threshold value makes it possible to make the identification of the subject as contaminated or non-contaminated independent of the basal value of the quantities measured in the subject, and therefore to reduce the risk error related to the variability of basal values from one subject to another.

It should also be noted that, for some individuals, the highest value reached by the indicative magnitude(s) measured may never exceed the positivity threshold allowing the actual contamination of the subject to be confirmed. This may in particular be the case of certain asymptomatic patients, or due to their metabolism. The use of the rate of change can thus make it possible to identify contaminated subjects who would potentially never have been identified by a simple comparison with a simple classical positivity threshold.

According to one embodiment, the subject is identified as contaminated or not contaminated with the pathogenic agent based on a comparison between the rate of change and the threshold value and a comparison between the additional variable with the first threshold and the second threshold.

Thus, the measurements taken on the additional sample are also used as such to rule out cases of non-contamination and validate cases of contamination.

According to one embodiment, if said subject has been identified as potentially contaminated with the pathogenic agent, the method further comprises:
- measuring, on a first and a second additional sample of said bodily fluid of said subject, the second additional sample being taken at a time interval t'' after the first additional sample, at least one indicative quantity;
- determining a rate of change over the time interval t'' of an indicative quantity, of the first variable or of an additional variable, and
- identifying the subject as contaminated or not contaminated by the pathogenic agent at least according to a comparison between the rate of change and a threshold value.

Like the first sample, the first additional sample and the second additional sample can be taken from the subject by known sampling methods, and are not intended to be reintroduced into the body of the subject after the implementation of the method.

The term "rate of change over the time interval t''" means a quantity which is representative of a temporal evolution of the quantity or variable considered during the time interval t'', i.e. between taking the first supplemental sample and the second supplemental sample. The rate of change can be a dimensionless quantity as well as a dimensioned quantity. The rate of change can thus be a dimensionless percentage change, a percentage change per unit time, a variation of a magnitude, or a variation of a magnitude per unit time.

Using the rate of change over the time interval t'' brings the same advantages as using the rate of change over the time interval t. These advantages are therefore not described in detail again. It will however be noted that one can measure on the first additional sample and the second additional sample one or more indicative quantities which would not have been measured on the first sample, the rate of change over the time interval t'' being determined using these indicative quantities.

Like the time interval t, the time interval t can be between 12 hours and 72 hours, more particularly between 24 hours and 48 hours.

According to one embodiment, the method further comprises:
- identifying the subject as being to be examined by a doctor and/or as having to undergo an additional sampling of bodily fluid if the rate of change is included in a predetermined interval, one limit of which is the threshold value.

Thus, a subject whose rate of change is close to the threshold value but within the predetermined range may be reported to a physician and/or identified as requiring additional bodily fluid sampling, in order to confirm the subject's contamination.

According to one embodiment, the threshold value is determined as a function of at least one characteristic of the subject.

Thus, the threshold value can be adapted to the physiology of the subject, possibly on the basis of experience. This improves the performance of the method.

According to one embodiment, the threshold value allows detection of the contamination by comparing the rate of change with the threshold value with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20% , 10%, 5%, 2%, 1% or 0.1%.

According to one embodiment, the threshold value allows detection of the contamination by comparing the rate of change with the threshold value with a false positive rate of less than 60%, preferably less than 40%, more preferably still less than 20% , 10%, 5%, 2%, 1% or 0.1%.

According to one embodiment, the pathogen is a virus, in particular a coronavirus, for example SARS-CoV-2.

Thus, the method according to the invention can be used to stem an epidemic or a pandemic of coronavirus disease, in particular an epidemic or a pandemic of Covid-19.

According to one embodiment,
- the bodily fluid is blood; And
- said at least one indicative quantity comprises at least one of a quantity of pathogen-specific immunoglobulins G (IgG) in the blood and a quantity of pathogen-specific immunoglobulins M (IgM) in the blood.

Thus, the methods according to the invention can be implemented from blood samples. The collection of such samples is easy and minimizes the risk of contamination of the person responsible for taking the sample. In addition, compared to other bodily fluids, blood has the advantage of having a substantially homogeneous composition regardless of the region where it is taken from the subject, which avoids the defects associated with methods based on a sample. nasal, pharyngeal or buccal. IgGs and IgMs are present in significant quantities in the blood and with a homogeneous distribution of their concentration throughout the circulating blood, which facilitates their precise quantification.

According to one embodiment, the first threshold is between 0.05 times and 0.9 times the second threshold, preferably between 0.2 and 0.5 times the second threshold, more preferably between 0.3 and 0.4 times the second threshold.

Thus, the second threshold can be chosen as equal (or higher if necessary) to the threshold of an existing IgM and IgG detection device. It can be adapted to reduce the rate of false positives or to take into account the circumstances of the epidemic as already mentioned above. The first threshold being between 0.05 times and 0.9 times the second threshold, it tends to minimize the false negatives, and this more so if it is between 0.2 times and 0.5 times the second threshold, and even more if it is between 0.3 times and 0.4 times the second threshold.

In terms of early detection, if we consider, for example, a pathology for which we obtain an increase of +30% per day in the quantity of IgM in the blood, for a variable which should normally reach the value 1 (unit arbitrary) before the subject is identified as contaminated by comparison with the second threshold, the variable will reach the value 0.77 one day before, the value 0.59 two days before, the value 0.46 three days before, the value 0.35 four days before, 0.27 five days before and 0.21 six days before. Although in reality the progression of the quantity of IgM in the blood is obviously not exactly mathematical and geometric, this qualitative evaluation shows that we can potentially save several days on the date of detection of the contamination, even a week or so. more. This can make all the difference in controlling a pandemic and protecting exposed or fragile populations, or monitoring potential super-spreaders.

According to one embodiment, if the quantity of pathogen-specific immunoglobulins M in the blood is below a first immunity threshold and the quantity of pathogen-specific immunoglobulins G in the blood is greater than a second immunity threshold, the subject is identified as being in the recovery or immunity phase.

Thus, in the case where the method uses the quantification of IgM and IgG, it also makes it possible to identify subjects with acquired immunity due to past contamination by the pathogenic agent. This can avoid subjecting these subjects to additional diagnostic methods, by avoiding identifying the subject as potentially recently contaminated when in fact he is in the recovery and immunity phase.

According to one embodiment, said quantities of IgG and of IgM are measured by fluorescence or by bioluminescence, in particular by fluorescence.

The quantification of IgG and IgM by fluorescence or by bioluminescence presents an appreciable sensitivity, in particular the quantification by fluorescence. This further improves the sensitivity of the method, and therefore the early detection of potential contamination.

According to one embodiment, the first sample and, where applicable, the additional sample are blood samples obtained by finger sampling.

Finger sampling can be carried out very quickly using simple and known devices, including by poorly qualified personnel and outside the framework of a laboratory or hospital. It also avoids the handling and management of a large number of blood samples, which would be essential if the samples were taken by a conventional blood test. It can be performed frequently, and even daily if necessary, unlike a traditional blood test. Finally, the micro-drop of blood can be tested immediately on a disposable test medium. All these advantages together allow implementation of the methods according to the invention on a very large number of subjects, including in temporary structures dedicated to the general screening of the population or to the screening of members of a community such as a company. , which makes it possible to consider their implementation to help stem a Covid-19 epidemic or pandemic.

The invention also provides a method for monitoring the contamination of a subject by a pathogenic agent, the method comprising the fact of identifying at least once the subject as contaminated, potentially contaminated or not contaminated by the pathogenic agent by the method according to one of the embodiments described above and, if the subject is identified n times as not contaminated by the pathogenic agent, n being an integer greater than or equal to one, storing at least once in a memory the first variable, and:
i) determining at least one (n+1)-th variable by measuring, on an (n+1)-th sample of said bodily fluid of said subject, said at least one indicative quantity;
ii) determining a difference between the (n+1)-th variable and one of the variables stored in memory or a weighted average of at least some of the variables stored in memory; And
iii) re-identifying the subject as contaminated, potentially contaminated or not contaminated with the pathogen at least based on a comparison of the difference with at least one additional threshold, and, if the subject is identified as not contaminated with the pathogen, store the (n+1)-th variable in memory,
steps i), ii) and iii) being repeated as long as the subject is identified as not contaminated in step iii).

This method is particularly useful for the regular monitoring of subjects who are particularly at risk, such as nursing staff, and who need to be checked at regular intervals. Indeed, for these subjects, the fact of identifying the subject as contaminated, potentially contaminated or not contaminated on the basis of a comparison of the difference with an additional threshold makes it possible to base the identification on the evolution of the indicative quantities measured, their basal level being eliminated when this difference is determined. If it turns out that the disease and/or the indicative values lead to variability in the basal level from one individual to another, the additional threshold may be reduced, and the sensitivity and early identification of subjects potentially contaminated or contaminated will be increased.

According to one embodiment, if the subject has been identified as potentially contaminated with the pathogenic agent in step (iii), the method further comprises:
iv) measuring, on an (n+2)-th sample of said bodily fluid of said subject taken at a time interval t' after the (n+1)-th sample, at least one indicative quantity;
v) determining a second rate of change of an indicative quantity, of the (n+1)-th variable or of a second additional variable between said samplings, and
vi) identifying the subject as contaminated or not contaminated with the pathogen at least based on a comparison between the second rate of change and an additional threshold value.

Thus, in the case where the subject is identified as potentially contaminated, its contamination or non-contamination by the pathogenic agent is confirmed using a rate of change over the interval t'. This makes it possible to obtain a good specificity as already explained above. The time interval t′ can be relatively short, for example between 12 hours and 72 hours, preferably between 24 hours and 48 hours, which makes it possible to relatively quickly confirm the contamination or the non-contamination of the subject.

According to one embodiment, the invention also provides a device for identifying subjects potentially contaminated with a pathogenic agent, the device comprising:
- a measurement unit configured to measure, on samples of bodily fluid from a subject, at least one quantity indicative of contamination of the subject by a pathogenic agent; And
- a processing unit configured to: determine at least a first variable on the basis of the results of a measurement carried out by the measurement unit on a first sample of said bodily fluid of the subject; comparing the first variable with a first threshold and a second threshold strictly greater than the first threshold; and identify:
a) the subject as contaminated by the pathogenic agent if the first variable is one of strictly greater than the second threshold and of strictly less than the first threshold;
b) the subject as potentially contaminated by the pathogenic agent if the first variable is between the first threshold and the second threshold;
c) the subject as not contaminated by the pathogenic agent if the first variable is the other of strictly greater than the second threshold and of strictly less than the first threshold.

Such a device has the same advantages as those previously described in connection with the method.

According to one embodiment, the invention also provides a method for monitoring the contamination by a pathogenic agent of a population comprising a plurality of subjects, the method comprising:
- for each subject, identifying, by the method according to any one of the embodiments described above, of the subject as contaminated, potentially contaminated, or not contaminated by the pathogenic agent;
- associating the identification of each subject at the time of identification and at least one item of information relating to the subject; And
- storing in a database the identifications thus associated and preferably the at least one indicative quantity measured.

Thus, the identifications and possibly the indicative quantities measured during the application of the method to a population of subjects can be made available to a human user for analysis and/or decision-making purposes. In particular, the measured indicative quantities stored in the database can be used to study the evolution over time of these indicative quantities in a large number of subjects.

According to one embodiment, the invention also provides a system for monitoring the contamination by a pathogenic agent of a population comprising a plurality of subjects, the system comprising:
- at least one device according to any one of the embodiments described above;
- an association unit configured to, on the basis of the identifications provided by said at least one device, associate the identification of each subject at the time of identification and at least one item of information relating to the subject; And
- a database configured to store the identifications associated by the association unit and preferably the at least one indicative quantity measured by the device.

According to one embodiment, the invention also provides a computer program comprising instructions which, when executed by a computer, lead the latter to implement the following steps:
- obtaining, from at least one device according to any one of the embodiments described above, identifications of each subject of a population of subjects as contaminated, potentially contaminated, or not contaminated by a pathogenic agent;
- associating the identification of each subject at the time of identification and at least one item of information relating to the subject; And
- storing in a database the identifications thus associated and preferably the at least one indicative quantity measured by the device.

According to one embodiment, the invention also provides a computer-readable recording medium on which the computer program described above is recorded.

According to one embodiment, the invention also provides a method for identifying subjects potentially contaminated with a pathogenic agent, the method comprising:
- detecting the presence, in a first sample of a body fluid of a subject, of at least one antibody and/or of at least one antigen indicative of the contamination of the subject by the pathogenic agent above a first predetermined detection threshold;
- if not, identify the subject as not contaminated by the pathogenic agent; And
- if so: identify the subject as potentially contaminated by the pathogenic agent; detecting the presence, in a second sample of said bodily fluid of said subject taken after the first sample, of said at least one antibody and/or at least one antigen above a second predetermined detection threshold above the first predetermined detection threshold; and identifying the subject as infected with the pathogen if so, and not infected with the pathogen if not.

A basic idea of this method is, analogously to the method already presented above, to identify as potentially contaminated a subject presenting an antibody and/or an antigen indicative of the contamination above a first threshold. of detection. This potentially contaminated subject can then, if the circumstances so require, be subject to temporary quarantine measures, until the people with whom he has been in contact can also be tested. The detection of the antibody and/or antigen above the second detection threshold then makes it possible to check whether the subject is actually contaminated. Thus, with this method, more contaminated or potentially contaminated subjects are identified, which makes it possible to take the necessary measures to protect the population earlier and to take care of patients earlier, improving their chances of recovery.

Brief description of figures

The invention will be better understood, and other aims, details, characteristics and advantages thereof will appear more clearly during the following description of several particular embodiments of the invention, given solely by way of illustration and not limitation. , with reference to the accompanying drawings.

FIG. 1 is a graph illustrating the fixing of the threshold of a diagnostic test of the state of the art, in the case of a discriminating quantitative test.

FIG. 2 is a graph similar to that of FIG. 1, illustrating the setting of the threshold of a diagnostic test of the state of the art presenting false positives and false negatives.

FIG. 3 is a functional diagram representing a device for identifying subjects potentially contaminated with a pathogenic agent.

Figure 4 is a flowchart representing part of a method for identifying subjects potentially contaminated with a pathogen.

Figure 5 is a flow chart representing another part of the method of Figure 4.

Figure 6 is a flowchart representing another method of identifying subjects potentially contaminated with a pathogenic agent.

FIG. 7 is a flowchart representing part of a method for monitoring the contamination of a subject by a pathogenic agent.

Figure 8 is a flow chart representing another part of the method of Figure 7.

Figure 9 is a block diagram showing a system for tracking pathogen contamination of a population comprising a plurality of subjects.

FIG. 10 is a flowchart representing a method for monitoring contamination by a pathogenic agent of a population comprising a plurality of subjects.

Figure 11 is a flowchart showing another method of identifying subjects potentially contaminated with a pathogen.

We will first describe, with the aid of FIG. 3, a device 10 for identifying subjects potentially contaminated by a pathogenic agent.

As represented in FIG. 3, the device 10 comprises a processing unit 11 and a measurement unit 12. The measurement unit 12 comprises a quantification unit 13 and a working zone 14. The working zone 14 is capable of receiving a sample 21 of a bodily fluid from a subject. The sample 21 is typically carried on a disposable support 20 adapted to receive the sample 21. The quantification unit 13 is capable of measuring at least one quantity on the sample 21 when the latter is introduced, thanks to the support 20 , in work area 14.

The support 20 is preferably disposable and for single use, which makes it possible to limit contamination between samples and the contamination of the person in charge of using the device 10. The support 20 can be of any known type, provided that it is adapted to receive the sample 21. According to a preferred example, the support 20 is a single-use disposable support capable of receiving a sample 21 which is a micro-drop of blood obtained by finger sampling. The methods for obtaining a micro-drop of blood by finger sampling are known as such and are therefore not reviewed in detail here. However, sample 21 may be a sample of another bodily fluid and/or may be taken by a different known method.

Thanks to the quantification unit 13, the measuring unit 12 is able to measure, on the sample 21, at least one quantity indicative of contamination of a subject by a pathogenic agent. In one example, the quantification unit 13 is capable of measuring a quantity of immunoglobulins G (hereinafter IgG) and/or a quantity of immunoglobulins M (hereinafter IgM) in the blood, for example by bioluminescence or by fluorescence, in particular by fluorescence. The IgGs and IgMs whose quantities are measured by the quantification unit 13 are of course specific to the pathogenic agent in order to make it possible to identify potential contamination of the subject by this pathogenic agent.

The pathogen can be a virus, in particular a coronavirus, for example SARS-CoV-2.

The device 10 further comprises a processing unit 11 able to acquire and process the measurements performed by the quantification unit 13 of the measurement unit 12. The device 10 also typically comprises a memory 15 in communication with the unit processing unit 11 for storing the results of measurements carried out by the measuring unit 12 and/or the results of processing carried out by the processing unit 11.

The device 10 can further comprise a user interface 16. The user interface 16 can comprise an input means 17 usable by the person in charge of using the device 10, for example to trigger a measurement by the quantification unit 13 after the support 20 has been introduced into the working area 14. The user interface 16 may also comprise a display 18 configured to display the results of the measurement carried out by the measurement unit 12 and/or to display an identification produced by the processing unit 11 as will be detailed below.

The device 10 may further comprise a communication interface 19 capable of transmitting the results of the measurement carried out by the measurement unit 12 and/or an identification produced by the processing unit 11.

A description will now be given, using FIG. 4, of a method 100 for identifying subjects potentially contaminated with a pathogenic agent. The method 100 can be implemented using the device 10. Consequently, in the following, the steps of the method 100 will be detailed with reference to the device 10. However, it is quite obvious that the method 100 can be implemented by other means, as long as these are capable of implementing the steps of method 100.

The method 100 comprises a step 101 in which, using the measuring unit 12, on the sample 21, at least one quantity indicative of contamination by a pathogenic agent of the subject from which the sample was taken is measured. sample 21.

After step 101, one goes to step 102 in which, from the at least one indicative quantity measured in step 101, at least one variable V is determined.

We describe for the moment the case where a single variable V is determined in step 102. The variable V can simply be the value of a single quantity measured in step 101, a quantity calculated according to a single magnitude measured in step 101, or else a quantity calculated as a function of several magnitudes.

In the following, we describe the case where the variable V is a variable likely to increase during a period of time following the contamination of the subject by the pathogenic agent. When the variable V is determined from an amount of IgG and/or an amount of IgM in the blood, the variable V will generally increase during this period of time, the body of the subject secreting IgG and IgM during this time period. However, the following description can easily be generalized to the case where the variable V is a variable likely to decrease for a period of time following the contamination of the subject by the pathogenic agent, by suitably adapting the roles of the thresholds T1 and T2 described above. -After.

In step 103, the variable V is compared with a first threshold T1. If the variable V is strictly lower than the threshold T1, it can be considered that the variable V indicates an absence of contamination of the subject. The method 100 therefore passes to a step 104 in which the subject is identified as not contaminated.

If the subject is not identified as not contaminated by the comparison carried out in step 103, the method goes to a step 105 in which the variable V is compared with a second threshold T2. The second threshold T2 is strictly greater than the first threshold T1. If the variable V is strictly greater than the second threshold T2, it can be considered that the variable V indicates contamination of the subject. The method 100 therefore proceeds to a step 106 in which the subject is identified as contaminated.

If the subject is not identified as contaminated by the comparison performed in step 105, the variable V is between the first threshold T1 and the second threshold T2. It can be considered that the variable V indicates a potential contamination of the subject. The method 100 therefore proceeds to a step 107 in which the subject is identified as potentially contaminated.

Steps 103 to 107 can be carried out by the processing unit 11. The identification of the subject as not contaminated carried out at step 104, as contaminated carried out at step 106, or as potentially contaminated carried out at step 107 can be stored in memory 15 and/or displayed on display 18.

Thanks to the method 100, a subject identified as contaminated in step 106 can immediately be the subject of measures which are necessary to prevent him from contaminating other people, in particular his quarantine as well as that of his entourage. . A subject identified as potentially contaminated at step 107 may be immediately subject to temporary quarantine for a relatively short period, for example for one to three days, until their actual contamination is confirmed by an examination. medical and/or other diagnostic method. During this temporary quarantine, temporary quarantine and/or screening of persons with whom the subject has been in contact may be undertaken, without waiting for confirmation of the subject's contamination. In the case of a highly contagious disease such as Covid-19, such immediate temporary quarantine accompanied by temporary quarantine and/or screening of people with whom the subject has been in contact can make all the difference for the people with whom the subject has been in contact as well as for the community.

The threshold T1 and/or the threshold T2 can simply be thresholds fixed in advance for the whole of the population of subjects to be tested by the method 100. The threshold T2 can in particular be a threshold used in a method of diagnosis in existing vitro to distinguish between contamination and non-contamination. It is understood that the threshold T1, being fixed lower than the threshold T2, then makes it possible to detect contaminations which would not be detected by using only the threshold T2 earlier.

The threshold T1 can be between 0.05 times and 0.9 times T2, more particularly between 0.2 and 0.5 times T2, more particularly still between 0.3 and 0.4 times T2, and this in particular when the variable V is determined from an amount of IgG and/or an amount of IgM in the blood.

However, as a variant, the threshold T1 and/or the threshold T2 can be determined beforehand as a function of at least one characteristic of the subject. By “characteristic of the subject”, is meant any quantity or information capable of characterizing the physiology of the subject. Examples of such characteristics are, without limitation, the age, sex or weight of the subject or the presence of other pathologies.

The threshold T1 can be set so as to allow detection of non-contamination by comparison of the variable V with the threshold T1 with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%. The false negative rate can be considered for the whole population of subjects to be tested by the 100 method, without taking into account any characteristics of the subjects, or it can be considered for subsets of the population to be tested defined by one or more common characteristics of the subjects of these subsets. It should be noted that it is thus the threshold making it possible to distinguish between potential contamination and non-contamination which is fixed in such a way as to allow detection of non-contamination by comparison of the variable V with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%.

It should be noted that the more we choose to lower T1, the more we will be able to detect contamination in the very early phase, but the more false positives we will obtain before confirmation of contamination by a medical examination and/or another method. diagnostic. Nevertheless, method 100 can be implemented even at the start of a new pandemic, when the other diagnostic tests are not yet effective or sufficiently tested, or even in the absence of so-called “gold standard” tests. This justifies that with the 100 method, we choose to live with average, mediocre or poorly identified predictive values to ensure very early detection of contamination.

The threshold T2 can be determined so as to optimize a negative predictive value and a positive predictive value associated with detection of the contamination by comparing the variable V with the threshold T2. It will be noted that it is thus the threshold making it possible to distinguish between potential contamination and contamination which is determined in such a way as to optimize a negative predictive value and a positive predictive value associated with detection of the contamination by comparing the variable V with this threshold.

Alternatively, the threshold T2 can be set so as to allow detection of the contamination by comparison of the first variable V with the threshold T2 with a false positive rate of less than 60%, preferably less than 40%, even more preferably less than 20%, 10%, 5%, 2%, 1% or 0.1%. It will be noted that it is thus the threshold making it possible to distinguish between potential contamination and contamination which is determined in such a way as to allow detection of the contamination by comparison of the variable V with a false positive rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%.

As mentioned above, when the subject is identified as potentially contaminated at step 107, his contamination can be confirmed by a medical examination and/or another diagnostic method. However, as a variant, method 100 can also make it possible to confirm the presence or absence of contamination, as will be detailed below with reference to FIG. 5.

As represented in FIG. 5, when the subject is identified as potentially contaminated at step 107, the method 100 proceeds (as indicated by reference B in FIGS. 4 and 5) to a step 108 in which it is measured at the using the measurement unit 12, on a new sample, at least one quantity indicative of contamination by a pathogenic agent of the subject from which the sample measured in step 101 was taken. The new sample is taken at a time interval t after the sample measured in step 101. The time interval t may be provided to device 10 through user interface 16, for example.

Typically, the same quantities are measured in step 101 and in step 108; as a variant, in step 108, the same quantities can be measured as in step 101 as well as other quantities.

After step 108, the method 100 passes to a step 109 in which the variable V is again determined, this time from the quantities measured in step 108 instead of the quantities measured in step 101. As a variant, an additional variable V', calculated differently from variable V, can be determined a first time from the quantities measured in step 101 and a second time from the quantities measured in step 108.

After step 109, the method 100 goes to a step 110 in which a rate of change R is determined over the time interval t. In other words, the rate of change R is a rate of change between the draws of the samples measured in steps 101 and 108. For example, the rate of change R can be calculated simply by the expression R = (V(t )-V(0))/t, where V(t) designates the value of the variable V calculated from the quantities measured in step 108 and V(0) designates the value of the variable V calculated from the quantities measured in step 101, or by the expression R = (V'(t) – V'(0))/t, where V'(t) designates the value of the variable V' calculated from the quantities measured in step 108 and V'(0) designates the value of the variable V' calculated from the quantities measured in step 101. The rate of change R can also be calculated by simple difference, i.e. say that R = V(t) – V(0) or R = V'(t) – V'(0).

As a variant, the rate of change R can be a dimensionless quantity; for example, it can be calculated by the expression R = (V(t) – V(0))/V(0), the result can be expressed as a percentage. It can also be expressed as a percentage per unit time, i.e. R = (V(t) – V(0))/(t x V(0)).

According to another variant, step 109 is omitted and the rate of change R determined at step 110 is simply determined from the quantities measured at step 101 and at step 108, without determining any variable from these sizes.

After step 110, the method 100 goes on to identify the subject as contaminated or not contaminated by the pathogenic agent at least according to a comparison between the rate of change R and a threshold value R1.

In the example represented in FIG. 5, after step 110, the method 100 passes to a step 111 in which the rate of change R determined in step 109 is compared with a threshold value R1. Since the variable V is likely to increase for a period of time following the contamination of the subject by the pathogenic agent, it can be considered that a strongly positive rate of change R indicates contamination of the subject by the pathogenic agent. If the rate of change R is greater than or equal to the threshold value R1, which is typically strictly positive, the method 100 then proceeds to a step 112 in which the subject is identified as contaminated. If, on the contrary, the rate of change R is strictly less than the threshold value R1, the method goes to a step 113 in which the subject is identified as not contaminated.

Steps 108 to 113 can be performed by the processing unit 11. The identification of the subject as contaminated carried out at step 112, or as contaminated carried out at step 113, can be stored in the memory 15 and/or displayed on display 18.

Of course, the foregoing can easily be generalized to the case where the variable V and V' is likely to decrease for a period of time following the contamination of the subject by the pathogenic agent: the rate of change R is then compared to a value strictly negative threshold R1, and the subject is identified as contaminated if the rate of change R is less than or equal to the threshold value R1, and as not contaminated if the rate of change R is greater than the threshold value R1.

Determining a rate of change R and comparing it to the threshold value R1 as just described makes it possible to distinguish false positives from true positives. Indeed, in the initial phase of the disease, from the moment when the at least one indicative quantity becomes detectable, its evolution can be rapid, typically of the order of 10% to 100% per day, which allows, for a second measurement on the additional sample, to identify the subject as not contaminated, thereby eliminating false positives.

The threshold value R1 can simply be a threshold value fixed in advance for the entire population of subjects to be tested by the method 100. However, as a variant, the threshold value R1 can be determined beforehand according to at least one characteristic of the subject. By “characteristic of the subject”, is meant any quantity or information capable of characterizing the physiology of the subject. Examples of such characteristics are, without limitation, the age, sex or weight of the subject or the presence of other pathologies.

The threshold value R1 can be set so as to allow detection of the contamination by comparing the rate of change R with the threshold value R1 with a rate of false negatives lower than 60%, preferably lower than 40%, more preferably still lower at 20%, 10%, 5%, 2% 1% or 0.1%. The false negative rate can be considered for the whole population of subjects to be tested by the 100 method, without taking into account any characteristics of the subjects, or it can be considered for subsets of the population to be tested defined by one or more common characteristics of the subjects of these subsets.

In addition or as an alternative, the threshold value R1 can be set so as to allow detection of the contamination by comparing the rate of change R with the threshold value R1 with a false positive rate of less than 60%, preferably less than 40 %, more preferably still less than 20%, 10%, 5%, 2% 1% or 0.1%. The false positive rate can be considered for the whole population of subjects to be tested by the 100 method, without taking into account any characteristics of the subjects, or it can be considered for subsets of the population to be tested defined by one or more common characteristics of the subjects of these subsets.

Alternatively, the subject can be identified as contaminated or not contaminated with the pathogen based on a comparison between the rate of change R and the threshold value R1 and at least one other criterion. In one example, the subject is identified as contaminated or not contaminated with the pathogen based on a comparison between the rate of change R1 and the threshold value R1 and a comparison between the variable V with the thresholds T1 and T2 . Thus, the measurements carried out on the additional sample can also be used as such to rule out cases of non-contamination and validate cases of contamination.

As a variant, in step 108, using the measuring unit 12, on two new samples, at least one quantity indicative of contamination by a pathogenic agent of the subject from which the sample measured in step 101. The two new samples are taken at a time interval t''. The time interval t'' can be provided to the device 10 through the user interface 16, for example.

In step 109, the variable V is then determined from the magnitudes measured in step 108 on the two new samples or an additional variable V′, calculated differently from the variable V.

After step 109, the method 100 goes to a step 110 in which a rate of change R is determined over the time interval t′ from the variable V or from the additional variable V′. The rate of change R can be calculated by formulas analogous to those mentioned above.

According to another variant, step 109 is omitted and the rate of change R determined in step 110 is simply determined from the quantities measured in step 108 on the two new samples, without determining any variable from these magnitudes.

As a variant, if the rate of change R is included in a predetermined interval, one limit of which is the threshold value R1, the subject is also identified as being to be examined by a doctor and/or as having to undergo an additional sample of bodily fluid.

Until now, the case where a single variable is determined in steps 102 and 109 has been described. However, when several quantities are measured on a sample, several variables can be determined from these quantities. A description will now be given, with reference to FIG. 6, of a method 200 implementing such a determination of several variables.

As represented in FIG. 6, the method 200 comprises a first step 201 in which, using the measuring unit 12, on the sample 21, several quantities Q1, ..., Qp indicative of contamination by a pathogen of the subject from which the sample was taken 21.

After step 201, the method 200 moves on to a step 202 consisting in verifying whether at least two of the quantities Q1, ..., Qp measured in step 201 meet a cure or immunity criterion. If so, the method 200 proceeds to a step 203 in which the subject is identified as cured or immune. The identification of the subject as cured or immunized made in step 203 can be stored in the memory 15 and/or displayed on the display 18.

When the indicative quantities Q1, …, Qp comprise a quantity of IgG in the blood and a quantity of IgM in the blood, the criterion of cure or immunity may consist in checking whether the quantity of IgM is less than one first immunity threshold and if the amount of IgG is greater than a second immunity threshold. Indeed, in this case, it can be considered that the organism has almost ceased to secrete IgM indicative of an ongoing contamination by the pathogenic agent, and that the organism of the subject is secreting IgG indicative of an immunity. .

Alternatively, steps 202 and 203 may be omitted, with method 200 then proceeding directly from step 201 to step 204. This may be the case when the disease caused by the pathogen does not generate immunity, or only generates it in a small proportion of subjects, or even when there is no criterion for cure or immunity.

In step 204, a plurality of variables V1, …, Vk are determined from the quantities Q1, …, Qp. Note that k is not necessarily equal to p, i.e. one can determine fewer, as many or more variables V1, …, Vk than there are quantities Q1, …, Qp. Each of the variables V1, … Vk can simply be the value of a single quantity measured in step 201, a quantity calculated according to a single quantity measured in step 201, or even a quantity calculated according to several magnitudes.

After step 204, the method 200 goes to a step 205 in which each of the variables V1, ..., Vk is compared with a single corresponding threshold or with two thresholds, one of which is strictly greater than the other. At least one of the variables V1, …, Vk is compared to two thresholds, one of which is strictly greater than the other. Naturally, each of the thresholds just mentioned can be specific to the variable V1, …, Vk which corresponds to it.

If, in step 205, at least one of the variables V1, ..., Vk is strictly greater than or strictly less than one of the two thresholds corresponding to it or to the unique threshold corresponding to it, it can be considered that this or these variables indicate contamination of the subject. The method then proceeds to a step 206 in which the subject is identified as contaminated. Otherwise, the method goes to a step 207.

If, in step 207, at least one of the variables V1, …, Vk is between the first threshold and the second threshold corresponding to it, it can be considered that this or these variables indicate a potential contamination of the subject. The method then proceeds to a step 208 in which the subject is identified as potentially contaminated. Otherwise, it can be considered that no variable indicates contamination of the subject. The method then proceeds to a step 209 in which the subject is identified as uncontaminated.

The identification of the subject as uncontaminated made in step 206, as contaminated made in step 208, or as potentially contaminated made in step 209 can be stored in the memory 15 and/or displayed on the display 18 .

If the subject is identified as potentially contaminated at step 208, his contamination can be confirmed by a medical examination and/or another diagnostic method, or else by steps analogous to steps 108 to 113 described above. In the latter case, the steps 108 to 113 can be implemented by determining only rates of change of the variable or variables which indicated a potential contamination of the subject, or of these variables as well as other variables among the variables V1 , …, Vk, or of all the variables V1, …, Vk. In a variant, the subject is identified as contaminated if the rate of change of a variable V1, ..., Vk is greater than or less than a threshold value, depending on whether the variable V1, ..., Vk is likely to increase or decrease being for a period of time following contamination of the subject with the pathogenic agent. In another variation, the subject is identified as contaminated if the rates of change of two or more variables indicate contamination of the subject.

The methods 100 and 200 that have just been described can be implemented by the processing unit 11 suitably programmed for this purpose. Alternatively, the processing unit 11 can only determine the variables V1, ..., Vk from samples and store them in the memory 15, the steps of the methods 100 and 200 being implemented later from the variables V1, …, Vk obtained from memory 15 via communication interface 19.

A description will now be given, with the aid of FIG. 7, of a variant method that can be used for the regular monitoring of a subject, and which makes it possible to take into account the basal level of the indicative quantities measured in this subject.

As indicated by the references C in FIGS. 4 and 7, method 1000 according to this variant comprises the fact of identifying the subject at least once as contaminated, potentially contaminated or not contaminated by the pathogenic agent by method 100. If the subject is identified at least once as not contaminated by the pathogenic agent in step 104, the variable V is stored in a memory, for example in the memory 15, during a step 1001. As a variant, the subject can be identified n times as not contaminated by the pathogenic agent in step 104 during n successive implementations of the method 100, n being an integer greater than or equal to one. The variable V is then stored in memory at step 1001 during one, some or each of these implementations of the method 100.

In any case, after step 1001, the method 1000 passes to a step 1002 in which at least one indicative quantity is measured on a new sample of the subject's bodily fluid. This indicative quantity is typically the same as that measured in step 101.

After step 1002, the method 1000 passes to step 1003 in which, from the at least one indicative quantity measured in step 1002, at least one variable V(n+1) is determined. The variable V(n+1) is typically the same as that determined in step 102.

After step 1003, method 1000 proceeds to step 1004 in which a difference is determined between variable V(n+1) and the last variable stored in memory at step 1001. Alternatively, step 1004 may consist in determining a difference between the variable V(n+1) and another of the variables stored in memory, or even a difference between the variable V(n+1) and a weighted average of at least some of the variables stored in memory. In any case, the difference determined in step 1003 represents a difference between the variable V(n+1) and a basal value determined previously in the subject.

After step 1004, the method 1000 proceeds to a step 1005 consisting of again identifying the subject as infected with the pathogen at least on the basis of a comparison of the difference determined in step 1004 with at least one additional threshold. For example, the subject can again be identified as uncontaminated if the difference is strictly less than a first additional threshold, as contaminated if the difference is strictly greater than a second additional threshold, and as potentially contaminated if the difference is between the first additional threshold and the second additional threshold.

After step 1005, the method thus passes to a step 1006 in which the subject is identified as contaminated, or to a step 1007 in which the subject is identified as not contaminated, or even to a step 1009 in which the subject is identified as potentially contaminated.

It will be noted that the at least one additional threshold will typically be different from the thresholds T1 and T2 selected to perform step 100. Indeed, this additional threshold is used for comparison with a difference between the variable V(n+1) and a value baseline determined previously in the subject. However, in general, prior knowledge of the basal values of the subject makes it possible to subtract them from successive measurements, and to set more effective thresholds for early detection of any future contamination. The additional threshold used in step 1005 therefore makes it possible to detect any contamination of the subject more precociously.

The identification of the subject as contaminated made at step 1006, as not contaminated made at step 1007, or as potentially contaminated made at step 1009 can be stored in the memory 15 and/or displayed on the display 18 .

When the subject is identified as uncontaminated at step 1007, method 1000 proceeds to step 1008 consisting of storing variable V(n+1) in memory with the other variables already stored in memory. Steps 1002 to 1005 can then be repeated identically from yet another new sample taken from the same subject. In particular, they can be repeated as long as the subject is identified as not contaminated.

When the subject is identified as potentially contaminated at step 1009, his contamination can be confirmed by a medical examination and/or another diagnostic method. However, as a variant, method 1000 can also make it possible to confirm the presence or absence of contamination, as will be detailed below with reference to figure 8.

As represented in FIG. 8, when the subject is identified as potentially contaminated at step 1009, the method 1000 passes (as indicated by the reference D in FIGS. 7 and 8) to a step 1009 in which one measures, on a new sample of bodily fluid from the subject, at least one indicative quantity. The new sample is taken at a time interval t' after the sample measured in step 1002. The time interval t' can be provided to the device 10 through the user interface 16, for example.

Typically, the same quantities are measured at step 1002 and at step 1009; as a variant, in step 1009, it is possible to measure the same quantities as in step 1009 as well as other quantities.

After step 1009, the method 1000 passes to a step 1010 in which the variable V(n+1) is again determined, this time from the quantities measured at step 1009 instead of the quantities measured at step 1002. As a variant, an additional variable V'(n+1), calculated differently from the variable V(n+1), can be determined a first time from the quantities measured in step 1002 and a second time from the quantities measured in step 1009.

After the step 1010, the method 1000 passes to a step 1011 in which a new rate of change R′ is determined over the time interval t′. In other words, the rate of change R' is a rate of change between the withdrawals of the samples measured in steps 1002 and 1009. For example, the rate of change R' can be calculated simply by the expression R' = ( V(n+1)(t') – V(n+1)(0))/t', where V(n+1)(t') designates the value of the variable V(n+1) calculated at from the quantities measured in step 1009 and V(n+1)(0) denotes the value of the variable V(n+1) calculated from the quantities measured in step 1002, or by the expression R′ = (V'(n+1)(t') – V'(n+1)(0))/t', where V(n+1)(t') designates the value of the variable V'(n +1) calculated from the quantities measured in step 1009 and V'(n+1)(0) designates the value of the variable V'(n+1) calculated from the quantities measured in step 1002. The rate of change R' can also be calculated by simple difference, i.e. R = V(n+1)(t') – V(n+1)(0) or R = V'( n+1)(t') – V'(n+1)(0).

As a variant, the rate of change R' can be a dimensionless quantity; for example, it can be calculated by the expression R' = (V(n+1)(t') – V(n+1)(0))/V(n+1)(0), the result being be expressed as a percentage. Alternatively, the rate of change R' can be expressed as a percentage per unit time, i.e. R' = (V(n+1)(t') – V(n+1)(0 ))/(t' x V(n+1)(0)).

In order to gain precision, as a variant, the rate of change R' can be determined from a variable previously determined and stored in memory or from a linear combination of several of these variables.

According to another variant, step 1010 is omitted and the rate of change R′ determined at step 1011 is simply determined from the quantities measured at step 1002 and at step 1009, without determining any variable from of these magnitudes.

After the step 1011, the method 1000 proceeds to the identification of the subject as contaminated or not contaminated by the pathogenic agent at least according to a comparison between the rate of change R′ and an additional threshold value R1′.

In the example represented in FIG. 8, after step 1011, the method 1000 passes to a step 1012 in which the rate of change R′ determined in step 1011 is compared with an additional threshold value R1′, and with a step 1013 if the subject is identified as contaminated, and a step 1014 if the subject is identified as not contaminated. Steps 1012 to 1014 are analogous to steps 111 to 113 and are therefore not described in detail again.

Alternatively, the rate of change R′ can be determined from two new samples measured in step 1009, analogously to what has already been mentioned in connection with method 100.

The identification of the subject as contaminated carried out at step 1013, or as not contaminated carried out at step 1014, can be stored in the memory 15 and/or displayed on the display 18.

If the subject is identified as uncontaminated at step 1014, the method proceeds to a step 1015 consisting in storing the variables V(n+1) determined at step 1002 and if necessary at step 1010 in memory with the other variables already stored in memory. As indicated by the reference E in FIGS. 7 and 8, steps 1002 to 1005, possibly supplemented by steps 1009 to 1015, can then be repeated identically from yet another new sample taken from the same subject. . In particular, they can be repeated as long as the subject is identified as not contaminated.

Of course, method 1000 can be performed at the end of step 200, one, some or all of the variables V1, ..., Vk being stored in memory when the subject is identified as potentially contaminated at step 209. alternatively, the subject can be identified n times as not contaminated by the pathogenic agent at step 209 during n successive implementations of the method 200, n being an integer greater than or equal to one. One, some or all of the variables V1, ..., Vk are then stored in memory at step 1001 during one, some or each of these implementations of the method 200. Steps 1002 to 1008 and the case where appropriate 1009 to 1015 can then be implemented for one, some or all of the variables V1, …, Vk.

A description will now be given, using FIG. 9, of a system 2000 for monitoring contamination by a pathogenic agent of a population comprising a plurality of subjects.

The methods which have been described with the aid of FIGS. 4 to 8 can be used to screen subjects one by one in a population, for example using the device 10 represented in FIG. to aggregate the identifications obtained by such screening carried out on a population.

FIG. 9 represents in the form of a functional diagram the system 2000. As represented, the system 2000 comprises a plurality of devices 10-1, 10-2, ... 10-N identical to the device 10, and a processing system 2001 comprising a of association 2003 and a database 2004.

In the example represented, the devices 10-1, 10-2, ..., 10-N communicate with the association unit 2003 via a communication interface 2002, for example on an Internet type network. However, as a variant, the identifications and measurements recorded by the devices 10-1, 10-2, ..., 10-N can be transmitted to the processing system 2001 via computer-readable recording media.

The association unit 2003 is configured to, on the basis of the identifications provided by the devices 10-1, 10-2, ..., 10-N, associate the identification of each subject at the time of identification and at the less information relating to the subject.

The identifications provided by devices 10-1, 10-2, …, 10-N are those obtained by implementing methods 100, 200 or 1000, and are provided by devices 10-1, 10-2, …, 10-N together with the time of identification. For example, when a subject is identified as contaminated, uncontaminated or potentially contaminated by one of the devices 10-1, 10-2, ..., 10-N, the subject can timestamp this identification and then provide the association unit 2003 with the identification together with the timestamp.

The association unit 2003 then associates this identification and this timestamp with at least one item of information relating to the subject. This may in particular be the place where the identification was carried out, medical information, a characteristic of the subject, or even a combination of such information, depending on the needs of the follow-up that one wishes to carry out at using System 2000.

The association unit 2003 is further configured to store in the database 2004 the identifications thus associated. Thus, the identifications and can be made available, via the 2004 database, to a human user for analysis and/or decision-making purposes.

In a preferred variant, the association unit 2003 also stores in the database 2004, in association with the identifications associated with at least one item of information relating to the subject, the at least one indicative quantity measured during the implementation of the method 100, 200 or 1000. The stored measured indicative quantities can thus be used to study the evolution over time of these indicative quantities in a large number of subjects.

Figure 10 is a flowchart depicting a method 3000 for tracking pathogen contamination of a population comprising a plurality of subjects. The 3000 method can be implemented by the 2000 system, the association unit 2003 being suitably programmed for this purpose. Alternatively, it can be implemented on a suitably programmed computer communicating with a database.

The method 3000 comprises a first step 3001 consisting in obtaining arrays 10-1, 10-2, ..., 10-N of the identifications of each subject of a population of subjects as contaminated, potentially contaminated, or not contaminated. After step 3001, the method 3000 proceeds to a step 3002 consisting of associating the identification of each subject at the time of identification and at least one item of information relating to the subject. After step 3002, the method 3000 passes to a step 3003 consisting in storing in a database the identifications thus associated and preferably the at least one indicative quantity measured by the device during the identification of the subject.

We will now describe, with the aid of FIG. 14, another method 4000 for identifying subjects potentially contaminated by a pathogenic agent. This method is based on the qualitative identification of at least one antibody and/or at least one antigen indicative of contamination of the subject by the pathogen at two different predetermined detection thresholds.

The method 4000 comprises a first step 4001 consisting in detecting the presence in a first sample of a body fluid of a subject, of at least one antibody and/or of at least one antigen indicative of the contamination of the subject by the pathogen above a first predetermined detection threshold. “Antibody indicative of the contamination of the subject by the pathogenic agent” means any antibody specific for the pathogenic agent and secreted by the body in the presence of the pathogenic agent. “Antigen indicative of the contamination of the subject by the pathogenic agent” means any antigen associated with the presence of the pathogenic agent in the body: it may in particular be an antigen carried by the pathogenic agent itself. even. The detection carried out in step 4001 is carried out by a technique suitable for detecting the antibody and/or the antigen, provided that a detection threshold can be associated with this technique; it can in particular be carried out by a lateral flow immunoassay or immunochromatography technique.

After step 4001, the method 4000 includes a step 4002 consisting in interpreting the result of the detection carried out in step 4001. If the detection concludes with the absence of the antibody and/or the antigen above of the first detection threshold, then the subject is identified as not contaminated during a step 4003.

Conversely, if the detection concludes with the presence of the antibody and/or of the antigen above the first detection threshold, then the subject is identified as potentially contaminated at step 4004.

After step 4004, one proceeds in a step 4005 to the detection of the presence of the antibody and/or of the antigen detected in step 4001 above a second predetermined detection threshold, in a second sample of the subject's bodily fluid. The detection carried out in step 4004 may or may not be carried out by the same technique as in step 4001. After step 4005, a step 4006 is carried out consisting in interpreting the result of the detection carried out in step 4005.

The second detection threshold is strictly greater than the first detection threshold; in other words, a positive detection at step 4004 indicates a stronger presence of the antibody and/or antigen in the second sample than in the first sample. Thus, if the detection is positive, it can be considered that the quantity of the antibody and/or of the antigen has increased between the collection of the first sample and the collection of the sample, and that the contamination by the agent pathogen has progressed in the subject between these samples. Therefore, if the detection concludes with the presence of the antibody and/or of the antigen above the second detection threshold, then the subject is identified as contaminated during a step 4007. Otherwise, the subject is identified as not contaminated during a step 4008.

Although the invention has been described in connection with several particular embodiments, it is obvious that it is in no way limited thereto and that it includes all the technical equivalents of the means described as well as their combinations if these fall within the scope of the invention.

The use of the verb "to comprise", "to understand" or "to include" and of its conjugated forms does not exclude the presence of other elements or other steps than those set out in a claim.

In the claims, any reference sign in parentheses cannot be interpreted as a limitation of the claim.

Claims (18)

A method (100) for identifying subjects potentially contaminated with a pathogenic agent, the method comprising:
- determining (102) at least one first variable (V) by measuring (101), on a first sample (21) of a bodily fluid from a subject, at least one quantity indicative of contamination of the subject by an agent pathogen;
- comparing the first variable (V) with a first threshold (T1) and a second threshold (T2) strictly greater than the first threshold, and
- identify:
a) the subject as contaminated (106) by the pathogenic agent if the first variable (V) is one of strictly greater than the second threshold (T2) and of strictly less than the first threshold (T1);
b) the subject as potentially contaminated (107) by the pathogenic agent if the first variable (V) is between the first threshold (T1) and the second threshold (T2);
c) the subject as not contaminated (104) by the pathogenic agent if the first variable (V) is the other of strictly greater than the second threshold (T2) and of strictly less than the first threshold (T1). Method according to claim 1, in which the first threshold (T1) and/or the second threshold (T2) are determined as a function of at least one characteristic of the subject. A method according to claim 1 or 2, wherein:
- or else the first variable (V) is a variable having the property of increasing for a period of time following the contamination of the subject by the pathogenic agent, and the subject is identified as:
a) contaminated with the pathogenic agent if the first variable (V) is strictly greater than the second threshold (T2);
b) potentially contaminated by the pathogenic agent if the first variable (V) is between the first threshold (T1) and the second threshold (T2);
c) not contaminated by the pathogenic agent if the first variable (V) is strictly lower than the first threshold (T1);
- or else the first variable (V) is a variable having the property of decreasing during a period of time following the contamination of the subject by the pathogenic agent, and the subject is identified as:
a) contaminated with the pathogenic agent if the first variable (V) is strictly lower than the first threshold (T1);
b) potentially contaminated by the pathogenic agent if the first variable (V) is between the first threshold (T1) and the second threshold (T2);
c) not contaminated by the pathogenic agent if the first variable (V) is strictly greater than the second threshold (T2). A method (200) according to any of claims 1 to 3, wherein:
- a plurality of first variables (V1, …, Vk) are determined by measuring, on the first sample, a plurality of quantities (Q1, …, Qp) indicative of contamination of the subject by a pathogenic agent;
- each of the first variables is compared with a first threshold and a second threshold strictly greater than the first threshold or a single threshold, and
- the subject is identified:
a′) as being in the recovery or immunity phase (203) if the measured values of at least two indicative quantities meet a recovery or immunity criterion;
b′) failing this, as contaminated (204) by the pathogenic agent if at least one of the first variables is strictly greater than or strictly less than one of the first corresponding threshold and of the second corresponding threshold or of the single threshold predetermined;
c′) failing that, as potentially contaminated (208) by the pathogenic agent if at least one of the first variables is between the corresponding first threshold and second threshold;
d') as uncontaminated (209) by the pathogen otherwise. Method according to any one of Claims 1 to 4, in which one of the first (T1) and of the second threshold (T2) allows detection of the contamination by comparison of the first variable (V) with the said threshold with a rate of false positives less than 60%, preferably less than 40%, more preferably even less than 20%, 10%, 5%, 2%, 1% or 0.1%, and the other of the first and the second threshold allows detection of non-contamination by comparison of the first variable (V) with said threshold with a false negative rate of less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5 %, 2%, 1% or 0.1%. Method according to any one of claims 1 to 5, in which one of the first (T1) and the second threshold (T2) is determined so as to optimize a negative predictive value and a positive predictive value associated with a detection of the contamination by comparing the first variable (V) with said threshold, and the other of the first and second thresholds allows detection of non-contamination by comparing the first variable (V) with said threshold with a rate of false negatives less than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%. A method according to any of claims 1 to 6, wherein if said subject has been identified as potentially infected with the pathogen, the method further comprises:
- measuring (108), on an additional sample of said bodily fluid of said subject taken at a time interval t after the first sample, at least one indicative quantity;
- determining (110) a rate of change (R) over the time interval t of an indicative quantity, of the first variable or of an additional variable, and
- identifying (111) the subject as contaminated (112) or not contaminated (113) by the pathogen at least according to a comparison between the rate of change (R) and a threshold value (R1). Method according to claim 7, in which the threshold value (R1) is determined as a function of at least one characteristic of the subject. Method according to claim 7 or 8, in which the threshold value (R1) allows detection of the contamination by comparing the rate of change (R) with the threshold value (R1) with a false negative rate of less than 60%, of preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%. Method according to any one of Claims 7 to 9, in which the threshold value (R1) allows detection of the contamination by comparing the rate of change (R) with the threshold value (R1) with a rate of false positives lower than 60%, preferably less than 40%, more preferably still less than 20%, 10%, 5%, 2%, 1% or 0.1%. Method according to any one of Claims 1 to 10, in which the first threshold (T1) is between 0.05 times and 0.9 times the second threshold (T2), preferably between 0.2 and 0.5 times the second threshold (T2), more preferably between 0.3 and 0.4 times the second threshold (T2). A method according to any of claims 1 to 11, wherein:
- the bodily fluid is blood; And
- said at least one indicative quantity comprises at least one of an amount of pathogen-specific immunoglobulins G in the blood and an amount of pathogen-specific immunoglobulins M in the blood. A method according to claim 12, wherein if the amount of pathogen-specific immunoglobulin M in the blood is below a first immunity threshold and the amount of pathogen-specific immunoglobulin G in the blood is greater than a second immunity threshold, the subject is identified as being in the recovery or immunity phase. A method (1000) of monitoring the contamination of a subject by a pathogenic agent, the method comprising the fact of identifying at least once the subject as contaminated, potentially contaminated or not contaminated by the pathogenic agent by the method (100 , 200) according to any one of claims 1 to 13, and, if the subject is identified n times as not contaminated by the pathogenic agent, n being an integer greater than or equal to one, storing (1001) at least once in a memory the first variable, and:
i) determining (1003) at least one (n+1)-th variable by measuring (1002), on an (n+1)-th sample of said bodily fluid of said subject, said at least one indicative quantity;
ii) determining (1004) a difference between the (n+1)-th variable and one of the variables stored in memory or a weighted average of at least some of the variables stored in memory; And
iii) identifying (1005) the subject again as contaminated (1006), potentially contaminated (1009) or not contaminated (1007) with the pathogen at least based on a comparison of the difference with at least one additional threshold , and, if the subject is identified as not contaminated by the pathogenic agent, storing (1008) the (n+1)-th variable in the memory,
steps i), ii) and iii) being repeated as long as the subject is identified as not contaminated in step iii). A method according to claim 14, wherein if the subject has been identified as potentially infected with the pathogen in step (iii), the method further comprises:
iv) measuring (1009), on an (n+2)-th sample of said bodily fluid of said subject taken at a time interval t' after the (n+1)-th sample, at least one indicative quantity;
v) determining (1011) a second rate of change over the time interval t' of an indicative quantity, of the (n+1)-th variable or of a second additional variable, and
vi) identifying (1012) the subject as contaminated (1013) or not contaminated (1014) with the pathogen at least based on a comparison between the second rate of change and an additional threshold value. Device (10) for identifying subjects potentially contaminated with a pathogenic agent, the device (10) comprising:
- a measurement unit (12) configured to measure, on samples (21) of bodily fluid from a subject, at least one quantity indicative of contamination of the subject by a pathogenic agent; And
- a processing unit (11) configured to: determine at least a first variable (V) on the basis of the results of a measurement carried out by the measurement unit (12) on a first sample (21) of said body fluid of the subject ; comparing the first variable (V) with a first threshold (T1) and a second threshold (T2) strictly greater than the first threshold; and identify:
a) the subject as contaminated by the pathogenic agent if the first variable (V) is one of strictly greater than the second threshold (T2) and of strictly less than the first threshold;
b) the subject as potentially contaminated with the pathogenic agent if the first variable (V) is between the first threshold (T1) and the second threshold (T2);
c) the subject as not contaminated by the pathogenic agent if the first variable (V) is the other of strictly greater than the second threshold (T2) and of strictly less than the first threshold (T1). A method (3000) for monitoring the contamination by a pathogenic agent of a population comprising a plurality of subjects, the method comprising:
- for each subject, identifying (3001), by the method according to any one of claims 1 to 13, of the subject as contaminated, potentially contaminated, or not contaminated by the pathogenic agent;
- associating (3002) the identification of each subject at the time of identification and at least one item of information relating to the subject; And
- storing (3003) in a database the identifications thus associated and preferably the at least one indicative quantity measured. Computer program comprising code instructions which, when the program is executed by a computer, lead it to implement the following steps:
- obtaining, from at least one device (10-1, 10-2, ..., 10-N) according to claim 16, identifications of each subject of a population of subjects as contaminated, potentially contaminated, or not contaminated by a pathogen;
- associating the identification of each subject at the time of identification and at least one item of information relating to the subject; And
- storing in a database (2004) the identifications thus associated and preferably the at least one indicative quantity measured by the device (10-1, 10-2, ..., 10-N).