Non-dits méthodologiques en recherche médicale

La pratique médicale moderne doit s’appuyer sur une « médecine fondée sur des faits prouvés » : mais qu’est ce qu’une preuve en médecine ? Pour certains philosophes, pour qu’il y ait preuve, il faut qu’il y ait croyance : quelles conséquences cela peut-il avoir dans le domaine médical ? Pourquoi doit-on tirer au sort l’allocation des traitements dans un essai thérapeutique ? Pour rendre les groupes semblables ? Mais pourtant, en cas de malchance, le déséquilibre peut être important… Cet article aborde plusieurs notions souvent utilisées par les méthodologistes : causalité, preuve, croyance, aléa, tirage au sort, modèle, observation, expérimentation, critère d’inclusion, mesure. L’objectif est de sortir du discours habituel, parfois un peu convenu, pour mettre en évidence quelques « non-dits » méthodologiques.Methodology consitutes the study of methods considered as « manners of leading its thought, of establishing or of showing truths according to certain principles and with a certain order ». We will see that medical « truths », knowledge, could be of an extremely different nature: factual knowledge is a simple observation, often with operational vocation; theoretical knowledge belongs to a coherent whole, it fascines and facilitates our representations of pathologies; the causal knowledge is often the subject of extreme interrogations in medical practice; it is of primarily metaphysical nature. These distinctions are not without consequence in methodological terms. Theories are useful because they facilitate the choice of the assumptions to be tested, the variables to be measured and the interpretation of the results of experiments. The risk however exists to be unable to think apart from their framework, and thus to neglect any source of knowledge which they could not integrate. The cause is inaccessible to science; it will be necessary, in practice, to be limited to the search for variables of upstream on which action of prevention or cure could be undertaken. To establish, to show this medical knowledge, it is necessary to resort to the scientific method by formulating refutable assumptions by reproducible experiments, and that this process involves a belief in the found results. It appears thus that for the same experimental plan, the level of belief and thus the level of proof of the results is a function of the type of measurement carried out (commonplace measurement or of high technicality), of the medical discipline and the media character or not of studied pathology, even of stakes of being able. The medical reproducibility of experiments is problematic since results of these experiments are in general random. This results from the considerable number of variables entering in the determination of human pathologies, and that the majority of these variables are either unknown, or impossible to control. Randomisation makes it possible to give a probabilistic character to this risk: it is then possible to resort to mathematics to carry out statistical tests, to calculate confidence intervals and to profit from a possibility of making inferences with a known margin of error. In the absence of randomisation, it is possible to resort to models; they imply however the knowledge of statistical methods, reserve, experience and a great intellectual honesty during the interpretation of the results, finally a replication of the experiments is here, more than elsewhere, essential

Statistical properties and privacy guarantees of an original distance-based fully synthetic data generation method

Introduction: The amount of data generated by original research is growing exponentially. Publicly releasing them is recommended to comply with the Open Science principles. However, data collected from human participants cannot be released as-is without raising privacy concerns. Fully synthetic data represent a promising answer to this challenge. This approach is explored by the French Centre de Recherche en {\'E}pid{\'e}miologie et Sant{\'e} des Populations in the form of a synthetic data generation framework based on Classification and Regression Trees and an original distance-based filtering. The goal of this work was to develop a refined version of this framework and to assess its risk-utility profile with empirical and formal tools, including novel ones developed for the purpose of this evaluation.Materials and Methods: Our synthesis framework consists of four successive steps, each of which is designed to prevent specific risks of disclosure. We assessed its performance by applying two or more of these steps to a rich epidemiological dataset. Privacy and utility metrics were computed for each of the resulting synthetic datasets, which were further assessed using machine learning approaches.Results: Computed metrics showed a satisfactory level of protection against attribute disclosure attacks for each synthetic dataset, especially when the full framework was used. Membership disclosure attacks were formally prevented without significantly altering the data. Machine learning approaches showed a low risk of success for simulated singling out and linkability attacks. Distributional and inferential similarity with the original data were high with all datasets.Discussion: This work showed the technical feasibility of generating publicly releasable synthetic data using a multi-step framework. Formal and empirical tools specifically developed for this demonstration are a valuable contribution to this field. Further research should focus on the extension and validation of these tools, in an effort to specify the intrinsic qualities of alternative data synthesis methods.Conclusion: By successfully assessing the quality of data produced using a novel multi-step synthetic data generation framework, we showed the technical and conceptual soundness of the Open-CESP initiative, which seems ripe for full-scale implementation

The improved Clinical Global Impression Scale (iCGI): development and validation in depression

BACKGROUND: The Clinical Global Impression scale (CGI) is frequently used in medical care and clinical research because of its face validity and practicability. This study proposes to improve the reliability of the Clinical Global Impression (CGI) scale in depressive disorders by the use of a semi-standardized interview, a new response format, and a Delphi procedure. METHODS: Thirty patients hospitalised for a major depressive episode were filmed at T1 (first week in hospital) and at T2 (2 weeks later) during a 5' specific interview. The Hamilton Depressive Rating Scale and the Symptom Check List were also rated. Eleven psychiatrists rated these videos using either the usual CGI response format or an improved response format, with or without a Delphi procedure. RESULTS: The new response format slightly improved (but not significantly) the interrater agreement, the Delphi procedure did not. The best results were obtained when ratings by 4 independent raters were averaged. In this situation, intraclass correlation coefficients were about 0.9. CONCLUSION: The Clinical Global Impression is a useful approach in psychiatry since it apprehends patients in their entirety. This study shows that it is possible to quantify such impressions with a high level of interrater agreement

Stratégies palliatives à la non-randomisation en santé mentale (score de propension et techniques d'ajustement apparentées. Méthodologie appliquée à la prise en compte des facteurs de confusion dans le cas de la schizophrénie)

Objectif : L objectif est l étude de plusieurs méthodes de prise en compte des facteurs de confusion, mesurés ou non mesurés, ce en situation observationnelle de population de patients psychotiques ou schizophrènes. Méthodes : Deux méthodes ont été utilisées : le score de propension (adaptés aux données mesurées) et les analyses de sensibilité (pour les informations non mesurées). Le champ d application est celui de l épidémiologie clinique en psychiatrie, et plus spécifiquement celui de la schizophrénie. Le développement s appuie sur trois parties successives. La première partie met en exergue la question de la discussion du biais résiduel. Pour cela, on s appuie sur les résultats d une étude transversale d exposition à un facteur contextuel (la prison), ce dans le cadre de la présence de troubles psychotiques (au sens axe DSM IV), à partir d une méthodologie d ajustement conventionnelle classique. La deuxième partie est une comparaison d une technique d ajustement classique à un ajustement par score de propension. Pour cela, on utilise les résultats issus d une étude de cohorte avec la survenue d un évènement selon l exposition à un traitement en population schizophrène, à partir de l utilisation du score de propension comme outil d ajustement. La troisième partie est une synthèse sur la modélisation de l incertitude et des biais de confusion non mesurés multiples. Les théories et méthodes sont décrites, puis appliquées aux résultats des deux études précédentes. Résultats : L étude transversale, dont les résultats non montrés jusqu à présent, permet de poser la problématique de la qualité de l ajustement dans le cadre d une exposition à un facteur en situation observationnelle. L étude de cohorte permet de comparer une technique d ajustement classique à un ajustement par score de propension (SP). Nous avons étudié plusieurs méthodes d ajustement (multivarié standard, avec ajustement sur SP, avec appariement sur SP). Et nous mettons en évidence que, selon la méthode d ajustement utilisée, les résultats obtenus sont différents. La méthode de stratification sur SP semble être la meilleure. Les méthodes de prise en compte des facteurs de confusion non mesurés sont ensuite étudiées. Une première étape fait état de l apport des théories probabilistes et des techniques apparentées, ensuite une combinaison de ces théories est proposée avec une application pratique aux deux études présentées précédemment. Conclusion : Dans le cas des études observationnelles, l objectif de ce travail a été d étudier, de décrire et d appliquer des techniques de modélisation pour mieux prendre en compte les différences initiales, potentiellement source de confusion. C est un travail à la frontière entre la méthodologie, les biostatistiques et l épidémiologie. Nous nous appuyons sur des difficultés rencontrées, en pratique en épidémiologie psychiatrique (pathologies mentales à étiologies multifactorielles et interdépendantes) pour proposer une approche pragmatique de la prise en compte optimale des facteurs de confusion potentiels, mesurés ou non mesurés.Objective : To evaluate control methods for measured or unmeasured confusion bias, in observational situation of psychotic or schizophrenic patients. Methods : Propensity score method (for measured confusion bias) and analyses of sensibility (for unmeasured confusion bias) were applied in the field of psychiatric epidemiology, specifically in schizophrenia. In first, the question of residual bias was underlined by the results of a transversal study. The exposition at a contextual parameter (prison) was studied in link with psychotic disorders (DSM IV), with a classic control method.Second, to lead to an unbiased estimation of treatment effect, we compared a classic control method with a method based on propensity score. These approach were applied to a cohort of French schizophrenic patients where we studied the event (relapse) by the treatment exposition (polypharmacy or not).Third, we developed a synthesis on modelisation of uncertainty and non-measured confusion bias. Theories and methods were described, and then applied on results of previous studies. Results : The transversal study, with non-demonstrated results still then, allow us to reach the question of control quality in the case of exposition to a parameter in observational situation. The cohort study permit to compare a classic control method and propensity score (PS). We highlighted different results according to some control method. Stratification method on PS seemed to be the best method to predict relapse according to treatment exposition. Non-measured bias control methods were then described. And a combination of probabilistic methods was applied to the previous studies. Conclusion : In the case of observational studies, the objective was to study, to describe and to apply modelisation methods to take in account differences at baseline, potentially source of confusion bias. This research is at the crossroads of methodology, biostatistics and epidemiology.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Which placebo to cure depression? A thought-provoking network meta-analysis

BACKGROUND: Antidepressants are often considered to be mere placebos despite the fact that meta-analyses are able to rank them. It follows that it should also be possible to rank different placebos, which are all made of sucrose. To explore this issue, which is rather more epistemological than clinical, we designed an unusual meta-analysis to investigate whether the effects of placebo in one situation are different from the effects of placebo in another situation. METHODS: Published and unpublished studies were searched for by three reviewers on Medline, the Cochrane Library, Embase, clinicaltrials.gov, Current Controlled Trial, in bibliographies, and by mailing key organizations. The following studies in first-line treatment for major depressive disorder were considered to construct an “evidence network”: 1) randomized controlled trials (RCTs) versus placebo on fluoxetine, venlafaxine and 2) fluoxetine versus venlafaxine head-to-head RCTs. Two network meta-analyses were run to indirectly compare response and remission rates among three different placebos: 1) fluoxetine placebo, 2) venlafaxine placebo, and 3) venlafaxine/fluoxetine placebo (that is, placebo compared to both venlafaxine and fluoxetine). Publication biases were assessed using funnel plots and statistically tested. RESULTS: The three placebos were not significantly different in terms of response or remission. The antidepressant agents were significantly more efficacious than the placebos, and venlafaxine was more efficacious than fluoxetine. The funnel plots, however, showed a major publication bias. CONCLUSION: The presence of significant levels of publication bias indicates that we cannot even be certain of the conclusion that sucrose equals sucrose in trials of major depressive disorder. This result should remind clinicians to step back to take a more objective view when interpreting a scientific result. It is of crucial importance for their practice, far more so than ranking antidepressant efficacy