Nicolas Savy

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Papers by Nicolas Savy

Use of Cumulative Poisson Probability Distribution as an Estimator of the Recombination Rate in an Expanding Population: Example of the Macaca fascicularis Major Histocompatibility Complex

G3 (Bethesda, Md.), 2012

We describe a method to estimate the rate of recombination per generation from the genotypes of a... more We describe a method to estimate the rate of recombination per generation from the genotypes of a large individual sample of an expanding population, for which the founding event is dated. The approach is illustrated with an application to estimating the major histocompatibility complex (MHC) recombination rate in the Mauritian macaque population. We genotyped 750 macaques by means of 17 microsatellites across the MHC region and reconstructed the seven most frequent haplotypes assumed to represent the founding haplotypes (H(rec(0))) as well as the 31% recombinant haplotypes (H(rec(h))) resulting from a variable number "h" of recombinations between the founding haplotypes. The relative frequencies of the various classes of haplotypes (H(rec(0)) and H(rec(h))) follow a Poisson distribution. By using a maximum likelihood method, we calculated the mean of the Poisson distribution that best fits the data. By dividing this mean by the number of generations (50-100) from the date...

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Survival curves of heated bacterial spores: effect of environmental factors on Weibull parameters

by Pierre Mafart and Nicolas Savy

International Journal of Food Microbiology, 2005

The classical D-value of first order inactivation kinetic is not suitable for quantifying bacteri... more The classical D-value of first order inactivation kinetic is not suitable for quantifying bacterial heat resistance for non-log linear survival curves. One simple model derived from the Weibull cumulative function describes non-log linear kinetics of micro-organisms. The influences of environmental factors on Weibull model parameters, shape parameter bpQ and scale parameter bdQ, were studied. This paper points out structural correlation between these two parameters. The environmental heating and recovery conditions do not present clear and regular influence on the shape the parameter bpQ and could not be described by any model tried. Conversely, the scale parameter bdQ depends on heating temperature and heating and recovery medium pH. The models established to quantify these influences on the classical bDQ values could be applied to this parameter bdQ. The slight influence of the shape parameter p variation on the goodness of fit of these models can be neglected and the simplified Weibull model with a constant p-value for given microbial population can be applied for canning process calculations. D

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Quantifying the combined effects of the heating time, the temperature and the recovery medium pH on the regrowth lag time of Bacillus cereus spores after a heat treatment

International Journal of Food Microbiology, 2005

The purpose of this study was to quantify the lag time of re-growth of heated spores of Bacillus ... more The purpose of this study was to quantify the lag time of re-growth of heated spores of Bacillus cereus as a function of the conditions of the heat treatment: temperature, duration and pH of the recovery medium. For a given heating temperature, curves plotting lag times versus time of heating show more or less complex patterns. However, under a heating time corresponding to a decrease of 2 decimal logarithms of the surviving populations of spores, a linear relationship between the lag time of growth and the time of the previous heat treatment can be observed. The slope of this linear relationship followed itself a Bigelow type linear relationship, the slope of which yielded a f-value very close to the observed conventional z-value. It was then concluded that the slope of the regrowth lag time versus the heating time followed a linear relationship with the sterilisation value reached in the course of the previous heat treatment. A sharp effect of the pH of the medium which could be described by a simple bsecondaryQ model was observed. As expected, the observed intercept of the linear relationship between lag time and heating time (lag without previous heating) was dependent on only the pH of the medium and not on the heating temperature. D

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Deleterious impact of feto-maternal MHC compatibility on the success of pregnancy in a macaque model

Immunogenetics, 2014

The impact of feto-maternal histocompatibility on reproduction has inspired long-lasting debates.... more The impact of feto-maternal histocompatibility on reproduction has inspired long-lasting debates. However, after the review of numerous articles, the impact of HLA allele sharing within couples on fecundity remains questionable. We decided to explore the impact of major histocompatibility complex (MHC) feto-maternal compatibility on reproduction in a cynomolgus macaque facility composed of animals of Mauritian descent. The Mauritian-derived macaque population presents a very restricted MHC polymorphism (only seven founding haplotypes) due to a strong founding bottleneck effect. The MHC polymorphism was investigated in 237 trios (male, female and offspring) using 17 microsatellite markers distributed across the MHC. Haplotypes were confirmed by segregation analysis. We evaluated the relative frequencies of MHC-compatible and MHC-semi-compatible offspring with the mothers. Among the 237 trios, we selected 42 trios for which the identity of the father is certain and for which the theoretical probabilities of fully compatible and semi-compatible offspring were equal. We found 11 offspring fully compatible and 31 offspring semi-compatible with their respective mother. The observed proportions were clearly outside the interval of confidence of 99 % and therefore most probably resulted from a selection of the semi-compatible offspring during pregnancy. We concluded that MHC fully compatible cynomolgus macaque offspring have a selective survival disadvantage in comparison with offspring inheriting a paternal MHC haplotype differing from maternal haplotypes.

Sharp large deviations for the non-stationary Ornstein–Uhlenbeck process

Stochastic Processes and their Applications, 2012

For the Ornstein-Uhlenbeck process, the asymptotic behavior of the maximum likelihood estimator o... more For the Ornstein-Uhlenbeck process, the asymptotic behavior of the maximum likelihood estimator of the drift parameter is totally different in the stable, unstable, and explosive cases. Notwithstanding this trichotomy, we investigate sharp large deviation principles for this estimator in the three situations. In the explosive case, we exhibit a very unusual rate function with a shaped flat valley and an abrupt discontinuity point at its minimum.

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Additive Cost Modelling in Clinical Trial

by Vladimir Anisimov and Nicolas Savy

Springer Proceedings in Mathematics & Statistics, 2014

ABSTRACT In the framework of a clinical trial, an important question is how long it takes to recr... more ABSTRACT In the framework of a clinical trial, an important question is how long it takes to recruit a given number n of patients. Until now, most techniques were based on deterministic models and various ad hoc techniques. Using a Poisson process to describe the recruitment process is now an accepted approach. However, in real trials, different centres have different recruitment rates. To mimic this variation, Anisimov and Fedorov (2007) used the so-called Poisson-gamma model in which the patients are assumed to arrive at different centres according to Poisson processes with Gamma-distributed rates. Here, we investigate the very first step of a cost model for multicentric clinical trial. This additive model describes the total cost C(t) of the trial at time t assuming patients arrive according to a Poisson-gamma process. To account for loss of patients during screening period, we also assume a patient can drop the trial at arrival with a centre-specific random probability; these probabilities are assumed Beta-distributed among centres. Filtered Poisson processes naturally arise in this model. Although these processes are not semi-martingales, we show we can calculate the expectation E[C(t)] where t is the (random) first time when the recruitment process reaches n.

Models for patients' recruitment in clinical trials and sensitivity analysis

Statistics in Medicine, 2012

Taking a decision on the feasibility and estimating the duration of patients' recruitment in a cl... more Taking a decision on the feasibility and estimating the duration of patients' recruitment in a clinical trial are very important but very hard questions to answer, mainly because of the huge variability of the system. The more elaborated works on this topic are those of Anisimov and co-authors, where they investigate modelling of the enrolment period by using Gamma-Poisson processes, which allows to develop statistical tools that can help the manager of the clinical trial to answer these questions and thus help him to plan the trial. The main idea is to consider an ongoing study at an intermediate time, denoted t 1 . Data collected on OE0; t 1 allow to calibrate the parameters of the model, which are then used to make predictions on what will happen after t 1 . This method allows us to estimate the probability of ending the trial on time and give possible corrective actions to the trial manager especially regarding how many centres have to be open to finish on time. In this paper, we investigate a Pareto-Poisson model, which we compare with the Gamma-Poisson one. We will discuss the accuracy of the estimation of the parameters and compare the models on a set of real case data. We make the comparison on various criteria : the expected recruitment duration, the quality of fitting to the data and its sensitivity to parameter errors. We discuss the influence of the centres opening dates on the estimation of the duration. This is a very important question to deal with in the setting of our data set. In fact, these dates are not known. For this discussion, we consider a uniformly distributed approach. Finally, we study the sensitivity of the expected duration of the trial with respect to the parameters of the model : we calculate to what extent an error on the estimation of the parameters generates an error in the prediction of the duration.

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On Ornstein-Uhlenbeck driven by Ornstein-Uhlenbeck processes

by Nicolas Savy and Frédéric Proïa

We investigate the asymptotic behavior of the maximum likelihood estimators of the unknown parame... more

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An omnibus test for several hazard alternatives in prevention randomized controlled clinical trials

by Valérie Gares and Nicolas Savy

Statistics in Medicine, 2014

The logrank test is optimal for testing the equality of survival distributions against a proporti... more The logrank test is optimal for testing the equality of survival distributions against a proportional hazards alternative. Under a late effects alternative, it is no longer appropriate, and one may turn to Fleming-Harrington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s class of weighted logrank tests instead. In some settings, such as in preventive clinical trials where the statistical analysis has to be designed before the trial begins, it can be difficult to choose a priori between the logrank and Fleming-Harrington tests. A solution to this issue is provided. A decision rule is constructed for the problem of testing the equality of two survival distributions when the expected alternative may be one of the proportional hazards and late effects. A formula for computing the necessary sample size is obtained for this decision rule. A comprehensive simulation study is conducted to assess finite sample properties of the proposed test statistic. The proposed test improves both the logrank test and Fleming-Harrington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s test for late effects. Finally, the methodology is illustrated on a data set in the field of prevention of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease.

Use of Cumulative Poisson Probability Distribution as an Estimator of the Recombination Rate in an Expanding Population: Example of the Macaca fascicularis Major Histocompatibility Complex

G3 (Bethesda, Md.), 2012

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Survival curves of heated bacterial spores: effect of environmental factors on Weibull parameters

by Pierre Mafart and Nicolas Savy

International Journal of Food Microbiology, 2005

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Quantifying the combined effects of the heating time, the temperature and the recovery medium pH on the regrowth lag time of Bacillus cereus spores after a heat treatment

International Journal of Food Microbiology, 2005

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Deleterious impact of feto-maternal MHC compatibility on the success of pregnancy in a macaque model

Immunogenetics, 2014