Bayesian predictive modeling for genomic based personalized treatment selection

Efforts to personalize medicine in oncology have been limited by reductive characterizations of the intrinsically complex underlying biological phenomena. Future advances in personalized medicine will rely on molecular signatures that derive from synthesis of multifarious interdependent molecular quantities requiring robust quantitative methods. However, highly-parameterized statistical models when applied in these settings often require a prohibitively large database and are sensitive to proper characterizations of the treatment-by-covariate interactions, which in practice are difficult to specify and may be limited by generalized linear models. In this paper, we present a Bayesian predictive framework that enables the integration of a high-dimensional set of genomic features with clinical responses and treatment histories of historical patients, providing a probabilistic basis for using the clinical and molecular information to personalize therapy for future patients. Our work represents one of the first attempts to define personalized treatment assignment rules based on large-scale genomic data. We use actual gene expression data acquired from The Cancer Genome Atlas in the settings of leukemia and glioma to explore the statistical properties of our proposed Bayesian approach for personalizing treatment selection. The method is shown to yield considerable improvements in predictive accuracy when compared to penalized regression approaches

Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set

BACKGROUND: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. METHODS: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan–Meier method. RESULTS: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R(2) = 0.73 and R(2) = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). CONCLUSIONS: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-016-0705-4) contains supplementary material, which is available to authorized users

Statistical Methods for Establishing Personalized Treatment Rules in Oncology

The process for using statistical inference to establish personalized treatment strategies requires specific techniques for data-analysis that optimize the combination of competing therapies with candidate genetic features and characteristics of the patient and disease. A wide variety of methods have been developed. However, heretofore the usefulness of these recent advances has not been fully recognized by the oncology community, and the scope of their applications has not been summarized. In this paper, we provide an overview of statistical methods for establishing optimal treatment rules for personalized medicine and discuss specific examples in various medical contexts with oncology as an emphasis. We also point the reader to statistical software for implementation of the methods when available

Bayesian learning of multiple essential graphs

L’apprendimento strutturale di modelli grafici e` un approccio consolidato all’identificazione di dipendenze complesse in reti biologiche. Presentiamo qui una metodologia bayesiana per l’apprendimento di reti orientate da dati osservazionali quando si osservino sottogruppi distinti di una popolazione.Structural learning of graphical models is a well-established approach to the identification of complex dependencies in biological networks. We here present a Bayesian methodology for learning directed networks from observational data when distinct subgroups of a population are observed

Multiple arrows in the Bayesian quiver: Bayesian learning of partially directed structures from heterogeneous data.

Motivated by the identification of complex dependencies in biological networks, we present a Bayesian method for structural learning of graphical models that exhibits two distinctive features: i) it does not assume a priori an ordering of the variables, but it learns arrows when possible and lines otherwise; ii) it assumes that the observations form subgroups having different but similar structures