A Bayesian Design Space for analytical methods based on multivariate models and predictions

in Journal of Biopharmaceutical Statistics (in press)

The International Conference for Harmonization (ICH) has released regulatory guidelines for Pharmaceutical Development. In the document ICH Q8, The Design Space of a process is presented as the set of ... [more ▼]

The International Conference for Harmonization (ICH) has released regulatory guidelines for Pharmaceutical Development. In the document ICH Q8, The Design Space of a process is presented as the set of factor settings providing satisfactory results. However, ICH Q8 does not propose any practical methodology to define, derive and compute Design Space. In parallel, in the last decades, it has been observed that the diversity and the quality of analytical methods have evolved exponentially allowing substantial gains in selectivity and sensitivity. However, there is still a lack for a rationale towards the development of robust separation methods in a systematic way. Applying ICH Q8 to analytical methods provides a methodology for predicting a region of the space of factors in which results will be reliable. Combining design of experiments and Bayesian standard multivariate regression, an identified form of the predictive distribution of a new response vector has been identified and used, under non-informative as well as informative prior distributions of the parameters. From the responses and their predictive distribution, various critical quality attributes can be easily derived. This Bayesian framework was then extended to the multi-criteria setting to estimate the predictive probability that several critical quality attributes will be jointly achieved in the future use of an analytical method. An example based on a high-performance liquid chromatography (HPLC) method is given. For this example, a constrained sampling scheme was applied to ensure the modeled responses have desirable properties. [less ▲]

Nonparametric additive location-scale models for interval censored data

in Statistics and computing (2013), 23

An nonparametric additive model for the location and dispersion of a continuous response with an arbitrary smooth conditional distribution is proposed. B-splines are used to specify the three components ... [more ▼]

An nonparametric additive model for the location and dispersion of a continuous response with an arbitrary smooth conditional distribution is proposed. B-splines are used to specify the three components of the model. It can deal with interval censored data and multiple covariates. After a simulation study, the relation between age, the number of years of full-time education and the net income (provided as intervals) available per person in Belgian households is studied from survey data. [less ▲]

Efficacy of pre-ascent climbing route visual inspection in indoor sport climbing

in Scandinavian Journal of Medicine & Science in Sports (2012), 22

Pre-ascent climbing route visual inspection (route preview) has been suggested as a key climbing performance para- meter although its role has never been verified experimentally. We examined the efficacy ... [more ▼]

Pre-ascent climbing route visual inspection (route preview) has been suggested as a key climbing performance para- meter although its role has never been verified experimentally. We examined the efficacy of this perceptual-cognitive skill on indoor sport climbing performance. Twenty-nine male climbers, divided into intermediate, advanced and expert climbing level groups, climbed two indoor sport routes matching their climbing level and, where applicable, routes below their climbing level. At each level, one route was climbed with a preview, where participants benefited from a 3-min pre-ascent climbing route visual inspection. Performance was assessed in terms of output (route comple- tion) and form (number and duration of moves and stops). Route preview did not influence the output performance. Climbers using visual inspection were no more likely to finish the ascent than those without the option of using visual inspection. Conversely, route preview did influence form performance; climbers made fewer, and shorter stops during their ascent following a preview of the route. Form performances differences remained when baseline ability levels were taken into account, although for shorter duration of stops only with expert climbers benefiting most from route preview. The ability to visually inspect a climb before its ascent may represent an essential component of performance optimization. [less ▲]

Comments on: Inference in multivariate Archimedean copulas models

in Test (2011), 20

Smooth semiparametric and nonparametric Bayesian estimation of bivariate densities from bivariate histogram data

in Computational Statistics & Data Analysis (2011), 55

Penalized B-splines combined with the composite link model are used to estimate a bivariate density from a histogram with wide bins. The goals are multiple: they include the visualization of the ... [more ▼]

Penalized B-splines combined with the composite link model are used to estimate a bivariate density from a histogram with wide bins. The goals are multiple: they include the visualization of the dependence between the two variates, but also the estimation of derived quantities like Kendall’s tau, conditional moments and quantiles. Two strategies are proposed: the first one is semiparametric with flexible margins modeled using B-splines and a parametric copula for the dependence structure; the second one is nonparametric and is based on Kronecker products of the marginal B-spline bases. Frequentist and Bayesian estimations are described. A large simulation study quantifies the performances of the two methods under different dependence structures and for varying strengths of dependence, sample sizes and amounts of grouping. It suggests that Schwarz’s BIC is a good tool for classifying the competing models. The density estimates are used to evaluate conditional quantiles in two applications in social and in medical sciences. [less ▲]

Use of Bayesian multivariate prediction models to optimize chromatographic methods

Conference (2010, May)

Pharmacokinetic parameters estimation using adaptive Bayesian P-splines models

in Pharmaceutical Statistics (2009), 8

In preclinical and clinical experiments, pharmacokinetic (PK) studies are designed to analyse the evolution of drug concentration in plasma over time i.e. the PK profile. Some PK parameters are estimated ... [more ▼]

In preclinical and clinical experiments, pharmacokinetic (PK) studies are designed to analyse the evolution of drug concentration in plasma over time i.e. the PK profile. Some PK parameters are estimated in order to summarize the complete drug’s kinetic profile: area under the curve (AUC), maximal concentration (Cmax), time at which the maximal concentration occurs (tmax) and half-life time (t1/2). Several methods have been proposed to estimate these PK parameters. A first method relies on interpolating between observed concentrations. The interpolation method is often chosen linear. This method is simple and fast. Another method relies on compartmental modelling. In this case, nonlinear methods are used to estimate parameters of a chosen compartmental model. This method provides generally good results. However, if the data are sparse and noisy, two difficulties can arise with this method. The first one is related to the choice of the suitable compartmental model given the small number of data available in preclinical experiment for instance. Second, nonlinear methods can fail to converge. Much work has been done recently to circumvent these problems (J. Pharmacokinet. Pharmacodyn. 2007; 34:229–249, Stat. Comput., to appear, Biometrical J., to appear, ESAIM P&S 2004; 8:115–131). In this paper, we propose a Bayesian nonparametric model based on P-splines. This method provides good PK parameters estimation, whatever be the number of available observations and the level of noise in the data. Simulations show that the proposed method provides better PK parameters estimations than the interpolation method, both in terms of bias and precision. The Bayesian nonparametric method provides also better AUC and t1/2 estimations than a correctly specified compartmental model, whereas this last method performs better in tmax and Cmax estimations. We extend the basic model to a hierarchical one that treats the case where we have concentrations from different subjects. We are then able to get individual PK parameter estimations. Finally, with Bayesian methods, we can get easily some uncertainty measures by obtaining credibility sets for each PK parameter. [less ▲]

Set up of a serum-free culture system for bovine embryos: embryo development and quality before and after transient transfer

in Theriogenology (2008), 69

It is well known that serum in culture medium negatively affects blastocyst quality. The objective of this work was to develop and test a serum-free culture medium which could improve embryo quality ... [more ▼]

It is well known that serum in culture medium negatively affects blastocyst quality. The objective of this work was to develop and test a serum-free culture medium which could improve embryo quality, measured by the resistance to freezing, lipid and glutathione content of the resulting blastocysts, as well as the ability of the blastocysts to elongate after transient transfer to recipient cows. In a first experiment we showed that adding a mixture of insulin, transferrin and selenium to serum-free Synthetic Oviduct Fluid medium (SOF–ITS) improved embryo development and quality. In the second experiment, the addition of BSA to SOF–ITS further improved blastocyst development. Moreover, a reduction in lipid content of morulae was observed in SOF–ITS–BSA by comparison with morulae cultured with serum (SOF–FCS). The resistance to freezing measured by hatching rates 24 h postthawing was also improved for blastocysts with a diameter between 160 and 180 mm cultured in SOF–ITS–BSA by comparison to those produced with serum. In order to evaluate the redox potential of the embryos, reduced glutathione content (GSH) was evaluated both before and after cryopreservation. A significant decrease in glutathione was observed after freezing, whatever the culture medium, but no difference was observed between culture conditions. Transient transfers were performed and elongated D- 13 embryos were recovered. Elongation was more pronounced and the embryonic disk more often visible in embryos cultured in SOF–ITS–BSA than in embryos cultured with FCS. In conclusion, the serum-free system we developed to produce in vitro bovine embryos meets the developmental and qualitative requirements for a large-scale use. [less ▲]

Effect of a collaborative approach on the quality of prescribing for geriatric inpatients: a randomized controlled trial

in Journal of the American Geriatrics Society (2007), 55(5), 658-665

OBJECTIVES: To evaluate the effect of pharmaceutical care provided in addition to acute Geriatric Evaluation and Management (GEM) care on the appropriateness of prescribing. DESIGN: Randomized, controlled ... [more ▼]

OBJECTIVES: To evaluate the effect of pharmaceutical care provided in addition to acute Geriatric Evaluation and Management (GEM) care on the appropriateness of prescribing. DESIGN: Randomized, controlled trial, with the patient as unit of randomization. SETTING: Acute GEM unit. PARTICIPANTS: Two hundred three patients aged 70 and older. INTERVENTION: Pharmaceutical care provided from admission to discharge by a specialist clinical pharmacist who had direct contacts with the GEM team and patients. MEASUREMENTS: Appropriateness of prescribing on admission, at discharge, and 3 months after discharge, using the Medication Appropriateness Index (MAI), Beers criteria, and Assessing Care of Vulnerable Elders (ACOVE) underuse criteria and mortality, readmission, and emergency visits up to 12 months after discharge. RESULTS: Intervention patients were significantly more likely than control patients to have an improvement in the MAI and in the ACOVE underuse criteria from admission to discharge (odds ratio (OR)=9.1, 95% confidence interval (CI)=4.2-21.6 and OR=6.1, 95% CI=2.2-17.0, respectively). The control and intervention groups had comparable improvements in the Beers criteria. CONCLUSION: Pharmaceutical care provided in the context of acute GEM care improved the appropriate use of medicines during the hospital stay and after discharge. This is an important finding, because only limited data exist on the effect of various strategies to improve medication use in elderly inpatients. The present approach has the potential to minimize risk and improve patient outcomes. [less ▲]

Robust specification of the roughness penalty prior distribution in spatially adaptive Bayesian P-splines models

in Computational Statistics & Data Analysis (2007), 51

The potential important role of the prior distribution of the roughness penalty parameter in the resulting smoothness of Bayesian Psplines models is considered. The recommended specification for that ... [more ▼]

The potential important role of the prior distribution of the roughness penalty parameter in the resulting smoothness of Bayesian Psplines models is considered. The recommended specification for that distribution yields models that can lack flexibility in specific circumstances. In such instances, these are shown to correspond to a frequentist P-splines model with a predefined and severe roughness penalty parameter, an obviously undesirable feature. It is shown that the specification of a hyperprior distribution for one parameter of that prior distribution provides the desired flexibility. Alternatively, a mixture prior can also be used. An extension of these two models by enabling adaptive penalties is provided. The posterior of all the proposed models can be quickly explored using the convenient Gibbs sampler. [less ▲]