Personalized cancer treatments based on the molecular profile of a patient's tumor are an emerging and exciting class of treatments in oncology. As genomic tumor profiling is becoming more common, targeted treatments for specific molecular alterations are gaining traction. To discover new potential therapeutics that may apply to broad classes of tumors matching some molecular pattern, experimentalists and pharmacologists rely on high-throughput, in vitro screens of many compounds against many different cell lines. We propose a hierarchical Bayesian model of how cancer cell lines respond to drugs in these experiments and develop a method for fitting the model to real-world high-throughput screening data. Through a case study, the model is shown to capture nontrivial associations between molecular features and drug response, such as requiring both wild type TP53 and overexpression of MDM2 to be sensitive to Nutlin-3(a). In quantitative benchmarks, the model outperforms a standard approach in biology, with $\approx20\%$ lower predictive error on held out data. When combined with a conditional randomization testing procedure, the model discovers markers of therapeutic response that recapitulate known biology and suggest new avenues for investigation. All code for the article is publicly available at https://github.com/tansey/deep-dose-response.

In the bioinformatics field, there has been a growing interest in modeling dihedral angles of amino acids by viewing them as data on the torus. This has motivated, over the past years, new proposals of distributions on the torus. The main drawback of most of these models is that the related densities are (pointwise) symmetric, despite the fact that the data usually present asymmetric patterns. This motivates the need to find a new way of constructing asymmetric toroidal distributions starting from a symmetric distribution. We tackle this problem in this article by introducing the sine-skewed toroidal distributions. The general properties of the new models are derived. Based on the initial symmetric model, explicit expressions for the shape and dependence measures are obtained, a simple algorithm for generating random numbers is provided, and asymptotic results for the maximum likelihood estimators are established. An important feature of our construction is that no extra normalizing constant needs to be calculated, leading to more flexible distributions without increasing the complexity of the models. The benefit of employing these new sine-skewed toroidal distributions is shown on the basis of protein data, where, in general, the new models outperform their symmetric antecedents.

Determining the effect of vaccine-induced immune response on disease risk is an important goal of vaccinology. Typically, immune correlates analyses are conducted prospectively with immune response measured shortly after vaccination and subsequent disease status regressed on immune response. In outbreaks and rare disease settings, collecting samples from all vaccinees is not feasible. The test negative design is a retrospective design used to measure vaccine efficacy where symptomatic individuals who present at a clinic are assessed for relevant disease (cases) or some other disease (controls) and vaccination status ascertained. This article proposes that test negative vaccinees have immune response to vaccine assessed both for relevant (e.g., Ebola) and irrelevant (e.g., vector) proteins. If the latter immune response is unaffected by active (Ebola) infection, and is correlated with the relevant immune response, it can serve as a proxy for the immune response of interest proximal to infection. We show that logistic regression using imputed immune response as the covariate and case disease as outcome can estimate the prospective immune response slope and detail the assumptions needed for unbiased inference. The method is evaluated by simulation under various scenarios including constant and decaying immune response. A simulated dataset motivated by ring vaccination for an ongoing Ebola outbreak is analyzed.

Recurrent event data are commonly encountered in observational studies where each subject may experience a particular event repeatedly over time. In this article, we aim to compare cumulative rate functions (CRFs) of two groups when treatment assignment may depend on the unbalanced distribution of confounders. Several estimators based on pseudo-observations are proposed to adjust for the confounding effects, namely inverse probability of treatment weighting estimator, regression model-based estimators, and doubly robust estimators. The proposed marginal regression estimator and doubly robust estimators based on pseudo-observations are shown to be consistent and asymptotically normal. A bootstrap approach is proposed for the variance estimation of the proposed estimators. Model diagnostic plots of residuals are presented to assess the goodness-of-fit for the proposed regression models. A family of adjusted two-sample pseudo-score tests is proposed to compare two CRFs. Simulation studies are conducted to assess finite sample performance of the proposed method. The proposed technique is demonstrated through an application to a hospital readmission data set.

Allele-specific copy number alteration (ASCNA) analysis is for identifying copy number abnormalities in tumor cells. Unlike normal cells, tumor cells are heterogeneous as a combination of dominant and minor subclones with distinct copy number profiles. Estimating the clonal proportion and identifying mainclone and subclone genotypes across the genome are important for understanding tumor progression. Several ASCNA tools have recently been developed, but they have been limited to the identification of subclone regions, and not the genotype of subclones. In this article, we propose subHMM, a hidden Markov model-based approach that estimates both subclone region and region-specific subclone genotype and clonal proportion. We specify a hidden state variable representing the conglomeration of clonal genotype and subclone status. We propose a two-step algorithm for parameter estimation, where in the first step, a standard hidden Markov model with this conglomerated state variable is fit. Then, in the second step, region-specific estimates of the clonal proportions are obtained by maximizing region-specific pseudo-likelihoods. We apply subHMM to study renal cell carcinoma datasets in The Cancer Genome Atlas. In addition, we conduct simulation studies that show the good performance of the proposed approach. The R source code is available online at https://dceg.cancer.gov/tools/analysis/subhmm. Expectation-Maximization algorithm; Forward-backward algorithm; Somatic copy number alteration; Tumor subclones.

Cancers are routinely classified into subtypes according to various features, including histopathological characteristics and molecular markers. Previous genome-wide association studies have reported heterogeneous associations between loci and cancer subtypes. However, it is not evident what is the optimal modeling strategy for handling correlated tumor features, missing data, and increased degrees-of-freedom in the underlying tests of associations. We propose to test for genetic associations using a mixed-effect two-stage polytomous model score test (MTOP). In the first stage, a standard polytomous model is used to specify all possible subtypes defined by the cross-classification of the tumor characteristics. In the second stage, the subtype-specific case-control odds ratios are specified using a more parsimonious model based on the case-control odds ratio for a baseline subtype, and the case-case parameters associated with tumor markers. Further, to reduce the degrees-of-freedom, we specify case-case parameters for additional exploratory markers using a random-effect model. We use the Expectation-Maximization algorithm to account for missing data on tumor markers. Through simulations across a range of realistic scenarios and data from the Polish Breast Cancer Study (PBCS), we show MTOP outperforms alternative methods for identifying heterogeneous associations between risk loci and tumor subtypes. The proposed methods have been implemented in a user-friendly and high-speed R statistical package called TOP (https://github.com/andrewhaoyu/TOP).

A popular way to control for unmeasured confounders is to utilize clusters (e.g. sets of siblings), in which a potentially large set of confounders are constant. By estimating the exposure-outcome association within clusters, rather than between unrelated subjects, all cluster-constant confounders are implicitly controlled for. To analyze such clustered data, it is common to use fixed effects models, which absorb all cluster-constant confounders into a cluster-specific intercept. In this article, we show how linear and log-linear fixed effects models can be used to estimate marginal counterfactual means. These counterfactual means can be estimated and presented for each exposure level separately, or contrasted to form a wide range of marginal causal effects. For binary outcomes, we propose to estimate marginal causal effects with marginal logistic between-within models. These models include a constant intercept common for all clusters, and control for unmeasured cluster-constant confounders by adding the mean exposure level in each cluster to the model. We illustrate the proposed methods by re-analyzing data from a co-twin control study on birth weight and Attention-Deficit/Hyperactivity Disorder.

Inferring brain connectivity network and quantifying the significance of interactions between brain regions are of paramount importance in neuroscience. Although there have recently emerged some tests for graph inference based on independent samples, there is no readily available solution to test the change of brain network for paired and correlated samples. In this article, we develop a paired test of matrix graphs to infer brain connectivity network when the groups of samples are correlated. The proposed test statistic is both bias corrected and variance corrected, and achieves a small estimation error rate. The subsequent multiple testing procedure built on this test statistic is guaranteed to asymptotically control the false discovery rate at the pre-specified level. Both the methodology and theory of the new test are considerably different from the two independent samples framework, owing to the strong correlations of measurements on the same subjects before and after the stimulus activity. We illustrate the efficacy of our proposal through simulations and an analysis of an Alzheimer's Disease Neuroimaging Initiative dataset.

With the increased availability of large electronic health records databases comes the chance of enhancing health risks screening. Most post-marketing detection of adverse drug reaction (ADR) relies on physicians' spontaneous reports, leading to under-reporting. To take up this challenge, we develop a scalable model to estimate the effect of multiple longitudinal features (drug exposures) on a rare longitudinal outcome. Our procedure is based on a conditional Poisson regression model also known as self-controlled case series (SCCS). To overcome the need of precise risk periods specification, we model the intensity of outcomes using a convolution between exposures and step functions, which are penalized using a combination of group-Lasso and total-variation. Up to our knowledge, this is the first SCCS model with flexible intensity able to handle multiple longitudinal features in a single model. We show that this approach improves the state-of-the-art in terms of mean absolute error and computation time for the estimation of relative risks on simulated data. We apply this method on an ADR detection problem, using a cohort of diabetic patients extracted from the large French national health insurance database (SNIIRAM), a claims database containing medical reimbursements of more than 53 million people. This work has been done in the context of a research partnership between Ecole Polytechnique and CNAMTS (in charge of SNIIRAM).