Papers by Jean-Pierre Boissel
Clinical Pharmacokinectics, 2006
In the field of drug noncompliance, we investigated an original approach that could give the pres... more 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. 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. 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. 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.
Journal of Theoretical Biology, Dec 1, 2006
With the aim to inhibit cancer growth and to reduce the risk of metastasis, pharmaceutical compag... more With the aim to inhibit cancer growth and to reduce the risk of metastasis, pharmaceutical compagnies developed early 90's anti-metastatic agents called inhibitors of metalloproteinases. Despite the promising results obtained in preclinic, results of phase III trials have been somewhat disappointing for late stage cancer patients. With the aim to investigate mathematically this therapeutic failure, we developed a mechanistic-based model which integrates cell cycle regulation and macroscopic tumor dynamic. By simulating the model, we evaluated the efficacy of metalloproteinases inhibitors therapies. Simulation results predict the lack of efficacy of metalloproteinases inhibitors in advanced cancer patients. The theoretical model may help the design of prospective clinical trials to evaluate the efficacy of antimetastatic therapies.
BMJ, Apr 11, 1992
cholecystectomy, however, is generally done by one person, and it is difficult for anyone other t... more cholecystectomy, however, is generally done by one person, and it is difficult for anyone other than the operating surgeon to observe what is taking place. How do Baxter and O'Dwyer propose to teach the minilaparotomy procedure to surgeons in training, particularly iffuture trainees have little or no experience with the open operation? Perhaps the most pressing reason for leaving minilaparotomy cholecystectomy out of the equation at this stage is that it is not yet recognised as a routine procedure.
Methods of Information in Medicine, 2003
Summary Objective: An assessment of the quality of health information on the Internet is an absol... more Summary Objective: An assessment of the quality of health information on the Internet is an absolute necessity. In this study ‘sensitive’ information was defined as information found in documents published on the Internet, which could be used in a medical decision. For sensitive information, the main criterion chosen for the quality of the information was an indication of the level of evidence. A survey was conducted using the CISMeF health catalogue to assess how often a score of the level of evidence is mentioned in the information accessible on the Internet in French-language health resources. Methods: Since 1999, members of the CISMeF team have systematically been searching for all documents containing ‘sensitive’ information and verifying whether the level of evidence was explicitly indicated as a score at least once in the document. Results: As of June 2001, 10,190 resources were included in CISMeF; including 2964 textual ‘sensitive’ resources (29.1%). Out of all these resourc...
Due to the scarcity of quantitative details about biological phenomena, quantitative modeling in ... more Due to the scarcity of quantitative details about biological phenomena, quantitative modeling in systems biology can be compromised, especially at the subcellular scale. One way to get around this is qualitative modeling because it requires few to no quantitative information. One of the most popular qualitative modeling approaches is the Boolean network formalism. However, Boolean models allow variables to take only two values, which can be too simplistic in some cases. The present work proposes a modeling approach derived from Boolean networks where continuous logical operators are used and where edges can be tuned. Using continuous logical operators allows variables to be more finely valued while remaining qualitative. To consider that some biological interactions can be slower or weaker than other ones, edge states are also computed in order to modulate in speed and strength the signal they convey. The proposed formalism is illustrated on a toy network coming from the epidermal g...
Due to the scarcity of quantitative details about biological phenomena, quantitative modeling in ... more Due to the scarcity of quantitative details about biological phenomena, quantitative modeling in systems biology can be compromised, especially at the subcellular scale. One way to get around this is qualitative modeling because it requires few to no quantitative information. One of the most popular qualitative modeling approaches is the Boolean network formalism. However, Boolean models allow variables to take only two values, which can be too simplistic in some cases. The present work proposes a modeling approach derived from Boolean networks where continuous logical operators are used and where edges can be tuned. Using continuous logical operators allows variables to be more finely valued while remaining qualitative. To consider that some biological interactions can be slower or weaker than other ones, edge states are also computed in order to modulate in speed and strength the signal they convey. The proposed formalism is illustrated on a toy network coming from the epidermal growth factor receptor signaling pathway. The obtained simulations show that continuous results are produced, thus allowing finer analysis. The simulations also show that modulating the signal conveyed by the edges allows to incorporate knowledge about the interactions they model. The goal is to provide enhancements in the ability of qualitative models to simulate the dynamics of biological networks while limiting the need of quantitative information.
Comptes Rendus Biologies, 2015
subunit. The results showed that when the oocytes were exposed to different concentration ACh for... more subunit. The results showed that when the oocytes were exposed to different concentration ACh for~2 s, the inward current mediated by mutant a3b2[F106V] nAChR could be recorded by two-electrode voltage clamp electrophsyiology. The mutant receptor had a higher sensitivity for ACh with a lower EC 50 of 28.9 mM, compared with wildtype a3b2 nAChR with an EC 50 of 95.9 mM. The b2 subunit mutant a3b2[F106V] nAChR was constructed successfully and functional, which indicates that F106 in loop E of b2 subunit plays a key role in sensitivity to the agonist ACh.
Comptes Rendus Biologies, 2014
Target identification, one of the steps of drug discovery, aims at identifying biomolecules whose... more Target identification, one of the steps of drug discovery, aims at identifying biomolecules whose function should be therapeutically altered in order to cure the considered pathology. This work proposes an algorithm for in silico target identification using Boolean network attractors. It assumes that attractors of dynamical systems, such as Boolean networks, correspond to phenotypes produced by the modeled biological system. Under this assumption, and given a Boolean network modeling a pathophysiology, the algorithm identifies target combinations able to remove attractors associated with pathological phenotypes. It is tested on a Boolean model of the mammalian cell cycle bearing a constitutive inactivation of the retinoblastoma protein, as seen in cancers, and its applications are illustrated on a Boolean model of Fanconi anemia. The results show that the algorithm returns target combinations able to remove attractors associated with pathological phenotypes and then succeeds in performing the proposed in silico target identification. However, as with any in silico evidence, there is a bridge to cross between theory and practice, thus requiring it to be used in combination with wet lab experiments. Nevertheless, it is expected that the algorithm is of interest for target identification, notably by exploiting the inexpensiveness and predictive power of computational approaches to optimize the efficiency of costly wet lab experiments.
Trends in Pharmacological Sciences, 1998
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 2009
The inflammatory process during stroke consists of activation of resident brain microglia and rec... more The inflammatory process during stroke consists of activation of resident brain microglia and recruitment of leucocytes, namely neutrophils and monocytes/macrophages. During inflammation, microglial cells, neutrophils and macrophages secrete inflammatory cytokines and chemokines, and phagocytize dead cells. The recruitment of blood cells (neutrophils and macrophages) is mediated by the leucocyte–endothelium interactions and more specifically by cell adhesion molecules. A mathematical model is proposed to represent the dynamics of various brain cells and of immune cells (neutrophils and macrophages). This model is based on a set of six ordinary differential equations and explores the beneficial and deleterious effects of inflammation, respectively phagocytosis by immune cells and the release of pro-inflammatory mediators and nitric oxide (NO). The results of our simulations are qualitatively consistent with those observed in experiments in vivo and would suggest that the increase of ...
European Journal of Cardiovascular Prevention & Rehabilitation, 2009
Numerous studies have examined the validity of available scores to predict the absolute cardiovas... more Numerous studies have examined the validity of available scores to predict the absolute cardiovascular risk. We developed a virtual population based on data representative of the French population and compared the performances of the two most popular risk equations to predict cardiovascular death: Framingham and SCORE. A population was built based on official French demographic statistics and summarized data from representative observational studies. The 10-year coronary and cardiovascular death risk and their ratio were computed for each individual by SCORE and Framingham equations. The resulting rates were compared with those derived from national vital statistics. Framingham overestimated French coronary deaths by 2.8 in men and 1.9 in women, and cardiovascular deaths by 1.5 in men and 1.3 in women. SCORE overestimated coronary death by 1.6 in men and 1.7 in women, and underestimated cardiovascular death by 0.94 in men and 0.85 in women. Our results revealed an exaggerated representation of coronary among cardiovascular death predicted by Framingham, with coronary death exceeding cardiovascular death in some individual profiles. Sensitivity analyses gave some insights to explain the internal inconsistency of the Framingham equations. Evidence is that SCORE should be preferred to Framingham to predict cardiovascular death risk in French population. This discrepancy between prediction scores is likely to be observed in other populations. To improve the validation of risk equations, specific guidelines should be issued to harmonize the outcomes definition across epidemiologic studies. Prediction models should be calibrated for risk differences in the space and time dimensions.
Computer Methods and Programs in Biomedicine, 1997
Meta-analysis of clinical trial data is an increasingly important method in clinical research, pa... more Meta-analysis of clinical trial data is an increasingly important method in clinical research, particularly in the field of therapeutic evaluation. This method uses some specific statistical techniques which are not all available on standard packages and therefore require specific developments. This paper describes a program designed to help medical researchers perform meta-analyses of clinical trial data with dichotomous outcomes. This program includes the various statistical methods of meta-analysis and enables cumulative meta-analysis and sub-groups to be performed. A robustness index can be determined and the results obtained in table and graphic formats. Data-editing and data-manipulating facilities are also possible. Much care has been taken to make the user interface as user-friendly as possible, so that the program is within the reach of all medical researchers.
Clinical Pharmacokinetics, 2002
Since it is difficult to improve patient compliance to drug prescriptions, an alternative is to s... more Since it is difficult to improve patient compliance to drug prescriptions, an alternative is to select a drug with less consequences for poor compliance, that is, a drug that has the capacity of 'forgiveness'. Forgiveness is the property of a drug which, when compared with another medicine with different pharmacokinetics and/or concentration-effect relationships, blunts the consequences of missing one or two doses in a row, or has a greater variability in the timing of intake. Simulations show that drugs with a concentration-effect relationship modelled with an effect compartment, for example a delayed response, have more forgiveness. A marker of forgiveness would be of some help for doctors deciding which drug to prescribe to patients who are poor compliers.
BMJ, 1992
renal failure to be assessed, taking into consideration Objective-To determine whether low protei... more renal failure to be assessed, taking into consideration Objective-To determine whether low protein the bias due to the various confounding factors (such as diets retard the development of end stage renal regression to the mean) and avoiding the use of disease. intermediate criteria (such as the slope of the time Design-Meta-analysis of 46 trials since 1975, course for the reciprocal values of serum creatinine from which six randomised controlled trials were concentration and the rate of decay of creatinine selected. clearance). Setting-Five trials in Europe and one in Australia between 1982 and 1991. Subjects-890 patients with mild to severe chronic Methods renal failure who were followed up for at least one The principle of meta-analysis entails the adjusted year. 450 patients received a low protein diet and 440 analysis of results in a collection of studies, with a a control diet. unique criterion for all studies. Meta-analysis is parti-Intervention-Difference in protein intake cularly suitable for studies of rare events in, for between control and treated groups of at least 0*2 g example, ponderous or longlasting trials that do not protein/kg/day. include many patients.9 The quality and impact of a Main outcome measure-Number of renal deaths meta-analysis depends on the selection process for the (the necessity to start dialysis or death of patient criterion, which must be well defined at the beginning during study). of the meta-analysis, and easily collected by non-Results-156 renal deaths were recorded, 61 in the specialist observers. low protein diet group and 95 in the control group, Definition ofa common event-We defined renal death leading to an odds ratio of low protein to control of as either the necessity to begin dialysis or the death of 0-54 with a 95% confidence interval of 0 37 to 0 79. patients during the study. Patients receiving grafts Conclusions-This result, obtained on a large before starting dialysis were counted as having had population of patients suffering from chronic renal renal death. Patients who were lost to follow up or who insufficiency, strongly supports the effectiveness of stopped taking the diet were not counted as having had low protein diets in delaying the onset of end stage renal death. These criteria were applied independently renal disease. of the randomised treatment by the authors on the basis of published data or complementary data kindly provided by the investigators.
CPT: Pharmacometrics & Systems Pharmacology, 2021
The value of in silico methods in drug development and evaluation has been demonstrated repeatedl... more The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk‐informed evaluation framework for mechanistic model credibility evaluation. To properly frame the proposed verification and validation activities, concepts such as context of use, regulatory impact and risk‐based analysis are discussed. To ensure common understanding between all stakeholders, an overview is provided of relevant in silico terminology used throughout this paper. To illustrate the feasibility of the proposed approach, we have applied it to three real case examples in the context of drug development, using a credibility matrix currently being tested as a quick‐start tool by regulators. Altogether, this white paper provides a practical approach to model ...
The Lancet, 2000
Celem metaanalizy była ocena ryzyka u pacjentów w wieku podeszłym z izolowanym nadciśnieniem skur... more Celem metaanalizy była ocena ryzyka u pacjentów w wieku podeszłym z izolowanym nadciśnieniem skurczowym, objętych programami prospektywnymi i randomizowanymi.
Nature Communications
Respiratory disease trials are profoundly affected by non-pharmaceutical interventions (NPIs) aga... more Respiratory disease trials are profoundly affected by non-pharmaceutical interventions (NPIs) against COVID-19 because they perturb existing regular patterns of all seasonal viral epidemics. To address trial design with such uncertainty, we developed an epidemiological model of respiratory tract infection (RTI) coupled to a mechanistic description of viral RTI episodes. We explored the impact of reduced viral transmission (mimicking NPIs) using a virtual population and in silico trials for the bacterial lysate OM-85 as prophylaxis for RTI. Ratio-based efficacy metrics are only impacted under strict lockdown whereas absolute benefit already is with intermediate NPIs (eg. mask-wearing). Consequently, despite NPI, trials may meet their relative efficacy endpoints (provided recruitment hurdles can be overcome) but are difficult to assess with respect to clinical relevance. These results advocate to report a variety of metrics for benefit assessment, to use adaptive trial design and adap...
ABSTRACTClinical research in infectious respiratory diseases has been profoundly affected by non-... more ABSTRACTClinical research in infectious respiratory diseases has been profoundly affected by non-pharmaceutical interventions (NPIs) against COVID-19. On top of trial delays or even discontinuation which have been observed in all disease areas, NPIs altered transmission pattern of many seasonal respiratory viruses which followed regular patterns for decades before the pandemic. Clinical trial design based on pre-pandemic historical data therefore needs to be put in question. In this article, we show how knowledge-based mathematical modeling can be used to address this issue. We set up an epidemiological model of respiratory tract infection (RTI) sensitive to a time dependent between-host transmission rate and coupled this model to a mechanistic description of viral RTI episodes in an individual patient. By reducing the transmission rate when the lockdown was introduced in the United Kingdom in March 2020, we were able to reproduce the perturbed 2020 RTI disease burden data. Using th...
PLOS ONE, 2015
Objective To examine the performances of an alternative strategy to decide initiating BP-lowering... more Objective To examine the performances of an alternative strategy to decide initiating BP-lowering drugs called Proportional Benefit (PB). It selects candidates addressing the inequity induced by the high-risk approach since it distributes the gains proportionally to the burden of disease by genders and ages. Study Design and Setting Mild hypertensives from a Realistic Virtual Population by genders and 10-year age classes (range 35-64 years) received simulated treatment over 10 years according to the PB strategy or the 2007 ESH/ESC guidelines (ESH/ESC). Primary outcomes were the relative lifeyear gain (life-years gained-to-years of potential life lost ratio) and the number needed to treat to gain a life-year. A sensitivity analysis was performed to assess the impact of changes introduced by the ESH/ESC guidelines appeared in 2013 on these outcomes. Results The 2007 ESH/ESC relative life-year gains by ages were 2%; 10%; 14% in men, and 0%; 2%; 11% in women, this gradient being abolished by the PB (relative gain in all categories = 10%), while preserving the same overall gain in life-years. The redistribution of benefits improved the profile of residual events in younger individuals compared to the 2007 ESH/ ESC guidelines. The PB strategy was more efficient (NNT = 131) than the 2013 ESH/ESC guidelines, whatever the level of evidence of the scenario adopted (NNT = 139 and NNT = 179 with the evidence-based scenario and the opinion-based scenario, respectively), although the 2007 ESH/ESC guidelines remained the most efficient strategy (NNT = 114).
Uploads
Papers by Jean-Pierre Boissel