Myriam Maumy-Bertrand

Reverse-engineering the genetic circuitry of a cancer cell with predicted intervention in chronic lymphocytic leukemia

Cellular behavior is sustained by genetic programs that are progressively disrupted in pathological conditions—notably, cancer. High-throughput gene expression profiling has been used to infer statistical models describing these cellular programs, and development is now needed to guide orientated modulation of these systems. Here we develop a regression-based model to reverse-engineer a temporal genetic program, based on relevant patterns of gene expression after cell stimulation. This method integrates the temporal dimension of biological rewiring of genetic programs and enables the prediction of the effect of targeted gene disruption at the system level. We tested the performance accuracy of this model on synthetic data before reverse-engineering the response of primary cancer cells to a proliferative (protumorigenic) stimulation in a multistate leukemia biological model (i.e., chronic lymphocytic leukemia). To validate the ability of our method to predict the effects of gene modulation on the global program, we performed an intervention experiment on a targeted gene. Comparison of the predicted and observed gene expression changes demonstrates the possibility of predicting the effects of a perturbation in a gene regulatory network, a first step toward an orientated intervention in a cancer cell genetic program.

Deviance residuals-based sparse PLS and sparse kernel PLS regression for censored data

MOTIVATION A vast literature from the past decade is devoted to relating gene profiles and subject survival or time to cancer recurrence. Biomarker discovery from high-dimensional data, such as transcriptomic or single nucleotide polymorphism profiles, is a major challenge in the search for more precise diagnoses. The proportional hazard regression model suggested by Cox (1972), to study the relationship between the time to event and a set of covariates in the presence of censoring is the most commonly used model for the analysis of survival data. However, like multivariate regression, it supposes that more observations than variables, complete data, and not strongly correlated variables are available. In practice, when dealing with high-dimensional data, these constraints are crippling. Collinearity gives rise to issues of over-fitting and model misidentification. Variable selection can improve the estimation accuracy by effectively identifying the subset of relevant predictors and enhance the model interpretability with parsimonious representation. To deal with both collinearity and variable selection issues, many methods based on least absolute shrinkage and selection operator penalized Cox proportional hazards have been proposed since the reference paper of Tibshirani. Regularization could also be performed using dimension reduction as is the case with partial least squares (PLS) regression. We propose two original algorithms named sPLSDR and its non-linear kernel counterpart DKsPLSDR, by using sparse PLS regression (sPLS) based on deviance residuals. We compared their predicting performance with state-of-the-art algorithms on both simulated and real reference benchmark datasets. RESULTS sPLSDR and DKsPLSDR compare favorably with other methods in their computational time, prediction and selectivity, as indicated by results based on benchmark datasets. Moreover, in the framework of PLS regression, they feature other useful tools, including biplots representation, or the ability to deal with missing data. Therefore, we view them as a useful addition to the toolbox of estimation and prediction methods for the widely used Coxs model in the high-dimensional and low-sample size settings. AVAILABILITY AND IMPLEMENTATION The R-package plsRcox is available on the CRAN and is maintained by Frédéric Bertrand. http://cran.r-project.org/web/packages/plsRcox/index.html. CONTACT pbastien@rd.loreal.com or fbertran@math.unistra.fr. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

A new universal resample-stable bootstrap-based stopping criterion for PLS component construction

We develop a new robust stopping criterion for partial least squares regression (PLSR) component construction, characterized by a high level of stability. This new criterion is universal since it is suitable both for PLSR and extensions to generalized linear regression (PLSGLR). The criterion is based on a non-parametric bootstrap technique and must be computed algorithmically. It allows the testing of each successive component at a preset significance level

Regression Tree for Bandits Models in A/B Testing

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Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

α. In order to assess its performance and robustness with respect to various noise levels, we perform dataset simulations in which there is a preset and known number of components. These simulations are carried out for datasets characterized both by

Late harvest as factor affecting esca and Botryosphaeria dieback prevalence of vineyards in the Alsace region of France

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