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Biomedical subjects

Jean-Pierre Boissel

Publications and source records attributed to Jean-Pierre Boissel.

At least 19 recordsLinked to original sources
PubMed2006

QxDB: a generic database to support mathematical modelling in biology.

QxDB (quantitative x-modelling database) is a web-based generic database package designed especially to house quantitative and structural information. Its development was motivated by the need for centralized access to such results for development of mathematical models, but its usefulness extends to the general research community of both modellers and experimentalists. Written in PHP (Hyper Preprocessor) and MYSQL, the database is easily adapted to new fields of research and ported to Apache-based web servers. Unlike most existing databases, experimental and observational results curated in QxDB are supplemented by comments from the experts who contribute input to the database, giving their evaluations of experimental techniques, breadth of validity of results, experimental conditions, and the like, thus providing the visitor with a basis for gauging the quality (or appropriateness) of each item for his/her needs. QxDB can be easily customized by adapting the contents of the database table containing the descriptors that characterize each data record according to an informal ontology of the research domain. We will illustrate this adaptability of QxDB by presenting two examples, the first dealing with modelling in oncology and the second with mechanical properties of cells and tissues.

Biology↗
PubMed2006

Why don't cancer patients enter clinical trials? A review.

Despite widespread agreement about the value of clinical trials, the proportion of patients who are enrolled in such trials is often considered to be too low. A comprehensive literature search was carried out for the period 1980 to the present, in order to review current data on barriers and facilitators to the development of multicentre clinical trials. Of 364 articles initially identified, 35 articles and 1 book were selected in order to assess the reasons that doctors and/or patients participate in clinical trials. This review emphasises the fact that doctors play a key role in the development and non-development of clinical trials. More studies, in particular studies outside the United States of America (USA), are needed in order better to understand doctors' attitudes towards clinical trials. Such studies should combine multivariate analyses and comparative approaches in order to associate doctors' behaviours with their individual characteristics, with the organisational context of their working environment and with the healthcare system.

Attitude of Health Personnel↗
PubMed2006

Literature search parameters marginally improved the pooled estimate accuracy for ultrasound in detecting deep venous thrombosis.

BACKGROUND AND OBJECTIVES: Data collection remains of utmost importance to avoid publication bias in systematic reviews. Our objectives were to compare search strategies with and without methodological terms in Medline, to find out how other databases complement Medline, and how these strategies affect the pooled estimates of the accuracy. STUDY DESIGN AND SETTING: A study was eligible if it prospectively compared ultrasound to venography for the diagnosis of deep venous thrombosis in the lower limbs. All relevant articles found with all databases, searched from 1966 through 2003, constitute the reference standard. Sensitivity was defined as the proportion of relevant studies found by Medline searches divided by the total number of articles in the reference standard. RESULTS: Of a total of 1,473 citations, 237 abstracts were included. The sensitivity of strategies without methodological terms was higher (96%) than those with (95%, 76%, and 95%). Searches of multiple databases found seven articles not found with Medline. Searches of congress proceedings (International Society of Thrombosis and Haemostasis) found three abstracts not published in full. The diagnostic odds ratio OR was 5.66 (95% confidence interval CI = 4.84-6.48) when multiple databases were searched and 5.57 (95% CI = 3.49-7.65) when only English-language articles in Medline were identified. CONCLUSION: Medline searches combining free text and MeSH terms were more sensitive. Single Medline search affects only marginally the pooled estimate accuracy.

Abstracting and Indexing↗
PubMed2006

Compliance-guided therapy : a new insight into the potential role of clinical pharmacologists.

BACKGROUND AND OBJECTIVE: In the field of drug noncompliance, we investigated an original approach that could give the prescribing physician, in collaboration with a clinical pharmacologist, an active role. The aim here is for the prescribing physician to take compliance into account so as to provide an optimised prescription (choice of molecule prescribed and its rhythm of administration) adapted to each patient. The example considered is that of oral anticoagulant treatment prescribed long-term. METHODS: In order to investigate the choice of the best molecule and treatment regimen for a given noncompliance pattern, we performed an in silico study with two oral anticoagulant agents, warfarin and acenocoumarol, each taken in one or two daily doses. Three linked models were used: the first model generated specific noncompliance patterns, the second model described the pharmacokinetics of oral anticoagulant agents and the third model summarised the pharmacokinetic-pharmacodynamic relations. RESULTS: Considering different patterns of noncompliance (including timing errors in drug intake and the phenomenon of drug holidays) and comparing warfarin with acenocoumarol, we identified different situations in which one agent (prescribed once or twice daily) could clearly minimise both the thromboembolic and haemorrhagic risks. However, for some specific noncompliance patterns, the choice of the optimal therapy should also be guided by the basal individual thromboembolic and haemorrhagic risks. CONCLUSION: Individualisation of drug therapy involves both drug dose and drug choice. In addition to the classical approach (i.e. drug level measurements, enzyme assays and even genetic sequence data), our study suggests that compliance-guided therapy may represent a potential, evolving way for the individualisation of prescriptions.

Humans↗
PubMed2005

A mathematical model of ion movements in grey matter during a stroke.

The development of cytotoxic oedema during a stroke consists in cell swelling and shrinking of the extracellular space. This phenomenon is triggered by ion movements through voltage-gated channels, exchangers and pumps. During ischaemia, sodium, calcium and chloride enter the neurons whereas potassium and glutamate are expelled out of the cells. A mathematical model is proposed to represent the long-term dynamics of membrane potentials, cell volumes and ionic concentrations in intracellular and extracellular spaces during a stroke and to study the influence of each ionic current on cell swelling. The model relies on electrophysiological mechanisms and takes into account the behaviour of two types of cells: neurons and also astrocytes known to play a key role in the excitotoxic process in grey matter. The results obtained when a severe or a moderate ischaemia is simulated are consistent with those observed in the in vitro and in vivo experiments. As this model appears to be robust, it is used to perform illustrative simulations aimed at studying the effect of some channel blockers on cell swelling. This approach may help to explore new therapeutic strategies in order to reduce stroke damage.

Astrocytes↗
PubMed2005

The true treatment benefit is unpredictable in clinical trials using surrogate outcome measured with diagnostic tests.

BACKGROUND AND OBJECTIVES: Clinical trials increasingly use results of diagnostic tests as surrogate outcomes. Our objective was to answer the following questions: (1) is the parameter measured by the reference standard a valid surrogate? (2) How does the tests accuracy influence the estimate of the treatment benefit on surrogate? (3) Is it possible to correct the measured treatment effect given by results of inaccurate tests? METHODS AND SETTING: We reviewed the literature on asymptomatic deep venous thrombosis (DVT), detected by the reference standard and other imaging techniques, as surrogate for venous thromboembolism. The influence of test inaccuracy on the measurement of treatment benefit was calculated as a function of the patient baseline risk, the treatment effect model, and test performances. RESULTS: We show that: (1) asymptomatic DVT is correlated with clinical outcomes but is yet to be established as a surrogate; (2) inaccurate diagnostic test underestimates the treatment effect on surrogate; (3) the prevalence of the disease, the treatment effect model, and the accuracy of the test and the reference standard used to evaluate it need to be known to correct this underestimation. CONCLUSION: Even when the surrogate end point is valid, without a reliable study of the diagnostic test we cannot quantify the true treatment effect.

Biomarkers↗
PubMed2005

How to measure non-consistency of medical practices with available evidence in therapeutics: a methodological framework.

Since the early 1980s many studies showed a gap between available evidence and medical practice. They were designed to assess the real impact of randomized clinical trials on the practice of medicine. Their results substantiated a knowledge translation problem. However, they were qualitative findings, i.e. a gap exists or not, although the problem is quantitative (how large is the gap?) and has several components that should be documented according to the objective of the study. In this article, we explored the components and the various contexts in which the measure of the distance between practice and knowledge is considered. All these features should be taken into account for a more accurate and relevant assessment of the distance.

Clinical Competence↗
PubMed2005

Apparent effect on blood pressure is only partly responsible for the risk reduction due to antihypertensive treatments.

The mechanism of risk reduction obtained by blood pressure-lowering pharmacological treatment remains unclear. We explored the amount of risk reduction attributable to the apparent effect of antihypertensive medicines on blood pressure by using the capture approach. Five randomized, placebo or nil controlled trials with a total of 28,997 subjects and 1,935 cardiovascular fatal or non-fatal events from the INDANA database met the eligibility criteria. Computations were performed on the original individual records using multiple Cox's proportional hazard regression models designed for meeting the assumed treatment mode of action and comparing relevant assumptions. For coronary event, the results are inconclusive essentially because the risk reduction is mild. However, for stroke the risk reduction adjusted for baseline risk factors is 34% (P<0.0001). The part explained by the effect of treatment on systolic blood pressure is 49% of this reduction, with 95% confidence interval not including 100%. This result suggests that the apparent effect on blood pressure is not the only cause of stroke risk reduction in hypertensive subjects submitted to an antihypertensive medicine.

Antihypertensive Agents↗
PubMed2004

Bridging the gap between therapeutic research results and physician prescribing decisions: knowledge transfer, a prerequisite to knowledge translation.

BACKGROUND: A wide gap continues to exist between available therapeutic research results and physician's prescribing. Numerous explanations account for this gap, but one central reason is the difficulty in transferring comprehensive research information to practicing clinicians. This problem arises from information overload and the growing complexity of research findings. We propose a multistep process that can be used to develop systems to bridge this information/prescription gap. The steps include: comprehensively collecting and summarizing clinical trial reports, scoring and ranking these according to their level of evidence, exploring and synthesizing the data using meta-analyses, summarizing these results, representing them in an easily understandable form, and transmitting the overview findings to prescribers at the time they need them. DISCUSSION: This ambitious endeavor is needed to ensure that prescribers have access to pertinent research results for use in their prescription decisions. We demonstrate in this article that there are no theoretical or technical obstacles to make the proposed system workable.

Clinical Competence↗
PubMed2004

Mathematical modelling of an ischemic stroke: an integrative approach.

Understanding the mechanisms and the time and spatial evolution of penumbra following an ischemic stroke is crucially important for developing therapeutics aimed at preventing this area from evolving towards infarction. To help in integrating the available data, we decided to build a formal model. We first collected and categorised the major available evidence from animal models and human observations and summarized this knowledge in a flow-chart with the potential key components of an evolving stroke. Components were grouped in ten sub-models that could be modelled and tested independently: the sub-models of tissue reactions, ionic movements, oedema development, glutamate excitotoxicity, spreading depression, NO synthesis, inflammation, necrosis, apoptosis, and reperfusion. Then, we figured out markers, identified mediators and chose the level of complexity to model these sub-models. We first applied this integrative approach to build a model based on cytotoxic oedema development following a stroke. Although this model includes only three sub-models and would need to integrate more mechanisms in each of these sub-models, the characteristics and the time and spatial evolution of penumbra obtained by simulation are qualitatively and, to some extent, quantitatively consistent with those observed using medical imaging after a permanent occlusion or after an occlusion followed by a reperfusion.

Animals↗
PubMed2004

Level of evidence and therapeutic evaluation: need for more thoughts.

The practice of evidence-based medicine requires a tool to assess and discriminate available data based on objective grounds, thus facilitating access to reliable information. The level of evidence, conceptually and practically embedded in scientific activity, allows comparing the results from multiple studies testing an identical hypothesis along the lines of at least two dimensions. The first dimension deals with the design of the study, i.e. the extent to which bias is avoided or managed, the second with the quality of incorporated data. A third dimension specific to therapeutic evaluation focuses on the clinical relevance of the tested hypothesis. The concern of the final user of the information is thus put to the fore. Indeed, a general practitioner will be interested in the benefit for its patients whereas the concern of a biologist might significantly diverge from the former matter. The bulk of existing scales of level of evidence concentrate on methodology. Some may include the second dimension but none embrace the three of them. Seldom considered are matters regarding reproducibility and procedure. This is all the more unfortunate as reproducibility is a cornerstone of scientific progress. Moreover, scales used for overviews fail to take into account the methodology designed to produce the synthesis. Inconsistent existing scales prevent the emergence of a generally agreed standard. Therefore, there is a need to further specify the concept of level of evidence in therapy evaluation and design scales encompassing the three above-mentioned dimensions: methodology of experiment, quality of data, and clinical relevance of the primary criterion.

Evidence-Based Medicine↗
PubMed2004

A systematic review of the accuracy of ultrasound in the diagnosis of deep venous thrombosis in asymptomatic patients.

Evaluation of the accuracy of ultrasound has yielded heterogeneous results. Our objective was to summarize the evidence on the accuracy of ultrasound compared to venography in asymptomatic patients, taking into account the variation due to threshold differences. Searches of journal table of contents, computer databases (Medline, Embase, Biomed, Cochrane) and conference proceedings were performed. A study was eligible if it prospectively compared ultrasound to venography for the diagnosis of DVT in asymptomatic patients. Data of studies selected for inclusion were extracted independently by two authors. High quality studies with consecutive patient enrollment, blind evaluation of the two techniques, and absence of verification bias are summarized as Level 1, while those not fulfilling one or more of these criteria are considered Level 2. Original study authors were contacted to confirm accuracy and to provide missing data. A pooled estimate of the accuracy of ultrasound was obtained according to the method of Moses and coworkers. This method gives a summary diagnostic odds ratio (DOR). The DOR is a single indicator of test performance. It varies between 0 and infinity and exceeds 1, only when ultrasound is more often positive in patients with DVT relative to those without DVT. Higher DOR indicates better discriminatory test performance. Thirty one studies were rated as potentially unbiased and graded as Level 1. The mean prevalence of DVT as determined by venography was 22%. In Level 1 studies, the odds of positive ultrasound in proximal veins was 379 times higher (95% confidence limits 65, 2,200) and in distal veins 32 times higher (7.5, 135) among patients with DVT than those without. Our results suggest that, particularly for proximal veins, ultrasound is accurate for the diagnosis of DVT in asymptomatic postoperative orthopedic patients. More research is needed in other clinical settings.

Humans↗
PubMed2003

Absolute benefit, number needed to treat and gain in life expectancy: which efficacy indices for measuring the treatment benefit?

The absolute benefit (AB) is extensively used to summarize the results of clinical trials. As the AB depends directly on the patient's baseline risk, therapeutic decisions based on AB tend to favor patients at high risk. To evaluate the consequences of this decision's procedure for life-long therapy, we compare the AB with the gain in event-free life expectancy in a simulated hypertensive population. Our results show that the AB goes through a maximum and then declines as the duration of treatment increases. The amplitude of the variation of AB is independent of the baseline risks but the maximum is reached more quickly in the high-risk patients. Considering the gain in event-free life expectancy, low-risk patients benefit more than high-risk patients do, at the expense of a longer treatment exposure. The interpretation of the AB changes depending on follow-up.

Adult↗
PubMed2003

Planning and monitoring of placebo-controlled survival trials: comparison of the triangular test with usual interim analyses methods.

AIMS: For ethical and economic reasons, interim analysis of phase III clinical trials is essential. This study was conducted to compare the efficiency of two interim analysis procedures, which could be used to allow early termination of a clinical trial. METHODS: We made a post hoc application of two interim analysis methods (Lan & DeMets with O'Brien-Flemming modification, and the triangular test according to Whitehead) by using individual patient data from four published placebo-controlled survival trials. We determined the date the trial would have been stopped had each method been used, and we estimated consequent results in terms of events and patient numbers included in the trial, the duration of the trial, and on treatment effect. RESULTS: The triangular test provided the lowest number of events required to reach a conclusion of the trials while providing an accurate estimate of experimental treatment effects. The triangular test thus indicated the smallest number of patients that would have been enrolled, and the shortest trial duration. The difference between the methods was most important with a detrimental effect of experimental treatment: the number of required events was reduced by 75% and the trial duration was shortened by 48% with the triangular test compared to the Lan & DeMets method. CONCLUSIONS: Stopping a trial early must depend on the clinical context. It is most important to stop a placebo-controlled trial as soon as possible when the experimental treatment can be shown deleterious. In such a situation the triangular test is more appropriate than the Lan & DeMets method. When a treatment effect is no different from, or better than, placebo the triangular test is also superior but the importance of premature termination of the trial in such cases has to be balanced against the inevitable reduction of information that the trial can provide.

Clinical Trials, Phase III as Topic↗
PubMed2003

How should therapeutic information be transferred to users?

Without an efficient solution to the problems that prevent prescribers and consumers having easy access to published and unpublished evidence, Evidence-Based Medicine will never become a reality. Among the problems, dissemination of the summarized evidence is a major one. It involves representing the summarized evidence in a format that corresponds to the users' needs and knowledge, interpreting it within the context of other related evidence, putting it in perspective, and then delivering it physically to the users at the appropriate time. The current formats, vehicles and representation models, e.g. those for guidelines or textbooks, do not seem efficient enough to fill in the gap of knowledge. We suggest that a new approach is possible by reducing the transferred information to its core and integrating it through appropriate representation models into the doctor's decision-making process.

Decision Making↗
PubMed2003

Pharmacogenetics and responders to a therapy: theoretical background and practical problems.

In a narrow meaning, responders to a therapy are all those who will react as expected following the administration of this therapy. However, a wider definition is worth considering: all those for whom the administration of the therapy will be beneficial. Innovative therapies are increasingly expensive and hazardous, and limiting prescriptions to responders is both economically and ethically compulsory. The theoretical basis for such an approach exists. The process of defining the profile of responders consists of identifying the characteristics of the patients that interact with the size of the effect and integrating them quantitatively in a predictive model. The effect model, which is the relation between the risks of the event with and without the treatment, can be used for the prediction. It can integrate interactions of the efficacy with risk factors and/or genes. The data to be used to achieve both the identification of the interactions and the building of the predictive model are those from the studied population, the set of patients enrolled in clinical trials. Hence, the process of defining the therapy is an extrapolation from the studied population. To carry out the extrapolation process one can use various available techniques, of which none fully fits the purpose. No method is currently both fully adequate and validated. Finally, the predictive models, which we need to identify responders, do not exist in practice. Fortunately, new research approaches have been developed recently.

Humans↗
PubMed2003

Getting evidence to prescribers and patients or how to make EBM a reality.

Bringing all available evidence on therapy efficacy to users is a necessary step in the evidence-based medicine paradigm. Today, the needs of physicians in medical information, including therapeutic information, are not met. Further, the information reaching the doctors is rarely consistent with the available evidence. The growth rate of emerging evidence and its increasing complexity make the doctors unable to cope with it within the current medical information system. So, there is a real need to sort out a new way for transferring therapeutic information to doctors and patients. We conceived a new paradigm and designed an Internet process based on it by which unbiased evidence is brought to doctors in such a format that it can be accessed and used during the visit.

Decision Support Systems, Clinical↗