On the combination of omics data for prediction of binary outcomes
Mar Rodríguez-Girondo, Alexia Kakourou, Perttu Salo, Markus Perola, Wilma E. Mesker, Rob A. E. M. Tollenaar, Jeanine Houwing-Duistermaat, Bart J. A. Mertens
Enrichment of predictive models with new biomolecular markers is an important task in high-dimensional omic applications. Increasingly, clinical studies include several sets of such omics markers available for each patient, measuring different levels of biological variation. As a result, one of the main challenges in predictive research is the integration of different sources of omic biomarkers for the prediction of health traits. We review several approaches for the combination of omic markers in the context of binary outcome prediction, all based on double cross-validation and regularized regression models. We evaluate their performance in terms of calibration and discrimination and we compare their performance with respect to single-omic source predictions. We illustrate the methods through the analysis of two real datasets. On the one hand, we consider the combination of two fractions of proteomic mass spectrometry for the calibration of a diagnostic rule for the detection of early-stage breast cancer. On the other hand, we consider transcriptomics and metabolomics as predictors of obesity using data from the Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) study, a population-based cohort, from Finland.
In many studies of human diseases, multiple omic datasets are measured. Typically, these omic datasets are studied one by one with the disease, thus the relationship between omics are overlooked. Modeling the joint part of multiple omics and its association to the outcome disease will provide insights into the complex molecular base of the disease. In this article, we extend dimension reduction methods which model the joint part of omics to a novel method that jointly models an outcome variable with omics. We establish the model identifiability and develop EM algorithms to obtain maximum likel…
Microbiome researchers often need to model the temporal dynamics of multiple complex, nonlinear outcome trajectories simultaneously. This motivates our development of multivariate Sparse Functional Principal Components Analysis (mSFPCA), extending existing SFPCA methods to simultaneously characterize multiple temporal trajectories and their inter-relationships. As with existing SFPCA methods, the mSFPCA algorithm characterizes each trajectory as a smooth mean plus a weighted combination of the smooth major modes of variation about the mean, where the weights are given by the component scores f…
High-throughput microarray and sequencing technology have been used to identify disease subtypes that could not be observed otherwise by using clinical variables alone. The classical unsupervised clustering strategy concerns primarily the identification of subpopulations that have similar patterns in gene features. However, as the features corresponding to irrelevant confounders (e.g. gender or age) may dominate the clustering process, the resulting clusters may or may not capture clinically meaningful disease subtypes. This gives rise to a fundamental problem: can we find a subtyping procedur…
Understanding of the pathophysiology of obstructive lung disease (OLD) is limited by available methods to examine the relationship between multi-omic molecular phenomena and clinical outcomes. Integrative factorization methods for multi-omic data can reveal latent patterns of variation describing important biological signal. However, most methods do not provide a framework for inference on the estimated factorization, simultaneously predict important disease phenotypes or clinical outcomes, nor accommodate multiple imputation. To address these gaps, we propose Bayesian Simultaneous Factorizati…
Multi-omics data, that is, datasets containing different types of high-dimensional molecular variables (often in addition to classical clinical variables), are increasingly generated for the investigation of various diseases. Nevertheless, questions remain regarding the usefulness of multi-omics data for the prediction of disease outcomes such as survival time. It is also unclear which methods are most appropriate to derive such prediction models. We aim to give some answers to these questions by means of a large-scale benchmark study using real data. Different prediction methods from machine …
Clustering is commonly performed as an initial analysis step for uncovering structure in 'omics datasets, e.g. to discover molecular subtypes of disease. The high-throughput, high-dimensional nature of these datasets means that they provide information on a diverse array of different biomolecular processes and pathways. Different groups of variables (e.g. genes or proteins) will be implicated in different biomolecular processes, and hence undertaking analyses that are limited to identifying just a single clustering partition of the whole dataset is therefore liable to conflate the multiple clu…
Background: State-of-the art selection methods fail to identify weak but cumulative effects of features found in many high-dimensional omics datasets. Nevertheless, these features play an important role in certain diseases. Results: We present Netboost, a three-step dimension reduction technique. First, a boosting-based filter is combined with the topological overlap measure to identify the essential edges of the network. Second, sparse hierarchical clustering is applied on the selected edges to identify modules and finally module information is aggregated by the first principal components. Th…
Large-scale {\it in vitro} drug sensitivity screens are an important tool in personalized oncology to predict the effectiveness of potential cancer drugs. The prediction of the sensitivity of cancer cell lines to a panel of drugs is a multivariate regression problem with high-dimensional heterogeneous multi-omics data as input data and with potentially strong correlations between the outcome variables which represent the sensitivity to the different drugs. We propose a joint penalized regression approach with structured penalty terms which allow us to utilize the correlation structure between …
Combining information from multiple samples is often needed in biomedical and economic studies, but the differences between these samples must be appropriately taken into account in the analysis of the combined data. We study estimation for moment restriction models with data combination from two samples under an ignorablility-type assumption but allowing for different marginal distributions of common variables between the two samples. Suppose that an outcome regression model and a propensity score model are specified. By leveraging the semiparametric efficiency theory, we derive an augmented …
Predicting the survival time of a cancer patient based on his/her genome-wide gene expression remains a challenging problem. For certain types of cancer, the effects of gene expression on survival are both weak and abundant, so identifying nonzero effects with reasonable accuracy is difficult. As an alternative to methods that use variable selection, we propose a Gaussian process accelerated failure time model to predict survival time using genome-wide or pathway-wide gene expression data. Using a Monte Carlo EM algorithm, we jointly impute censored log-survival time and estimate model paramet…
We develop a Bayesian approach to predict a continuous or binary outcome from data that are collected from multiple sources with a multi-way (i.e.. multidimensional tensor) structure. As a motivating example we consider molecular data from multiple 'omics sources, each measured over multiple developmental time points, as predictors of early-life iron deficiency (ID) in a rhesus monkey model. We use a linear model with a low-rank structure on the coefficients to capture multi-way dependence and model the variance of the coefficients separately across each source to infer their relative contribu…
Academy of Mathematics and Systems Science（数学与系统科学研究院）；Chinese Academy of Sciences（中国科学院）；School of Mathematical Sciences（数学科学学院）；University of Chinese Academy of Sciences（中国科学院大学）；University of California, Los Angeles（加利福尼亚大学洛杉矶分校）
Outcome labeling ambiguity and subjectivity are ubiquitous in real-world datasets. While practitioners commonly combine ambiguous outcome labels for all data points (instances) in an ad hoc way to improve the accuracy of multi-class classification, there lacks a principled approach to guide the label combination for all data points by any optimality criterion. To address this problem, we propose the information-theoretic classification accuracy (ITCA), a criterion that balances the trade-off between prediction accuracy (how well do predicted labels agree with actual labels) and classification …
The problem we consider considers estimating a multivariate longitudinal panel data model whose outcomes can be a combination of discrete and continuous variables. This problem is challenging because the likelihood is usually analytically intractable. Our article makes both a methodological contribution and also a substantive contribution to the application. The methodological contribution is to introduce into the panel data literature a particle Metropolis within Gibbs method to carry out Bayesian inference, using a Hamiltonian Monte Carlo (Neal 2011} proposal for sampling the vector of unkno…
Given two 2-level factors of interest, a 2^2 split-plot design} (a) takes each of the $2^2=4$ possible factorial combinations as a treatment, (b) identifies one factor as `whole-plot,' (c) divides the experimental units into blocks, and (d) assigns the treatments in such a way that all units within the same block receive the same level of the whole-plot factor. Assuming the potential outcomes framework, we propose in this paper a randomization-based estimation procedure for causal inference from 2^2 designs that are not necessarily balanced. Sampling variances of the point estimates are derive…
A pressing challenge in medical research is to identify optimal treatments for individual patients. This is particularly challenging in mental health settings where mean responses are often similar across multiple treatments. For example, the mean longitudinal trajectories for patients treated with an active drug and placebo may be very similar but different treatments may exhibit distinctly different individual trajectory shapes. Most precision medicine approaches using longitudinal data often ignore information from the longitudinal data structure. This paper investigates a powerful precisio…
In large epidemiologic studies, it is typical for an inexpensive, non-invasive procedure to be used to record disease status during regular follow-up visits, with less frequent assessment by a gold standard test. Inexpensive outcome measures like self-reported disease status are practical to obtain, but can be error-prone. Association analysis reliant on error-prone outcomes may lead to biased results; however, restricting analyses to only data from the less frequently observed error-free outcome could be inefficient. We have developed an augmented likelihood that incorporates data from both e…
Data-adaptive gene and pathway-based tests forrare-variant associations with survival outcomes
Medical College of Wisconsin（威斯康星医学院）；German Cancer Research Center (DKFZ)（德国癌症研究中心）；University of Leicester（莱斯特大学）；Instituto de Investigación Sanitaria de Santiago de Compostela（圣地亚哥-德孔波斯特拉卫生研究所）；Fundación Pública Galega de Medicina Xenómica（加利西亚公共基因组医学基金会）；Biomedical Network on Rare Diseases (CIBERER)（罕见病生物医学网络）；Icahn School of Medicine at Mount Sinai（西奈山伊坎医学院）；Cross Cancer Institute, University of Alberta（阿尔伯塔大学交叉癌症研究所）；University of Manchester（曼彻斯特大学）；Ghent University / Ghent University Hospital（根特大学/根特大学医院）
Powerful Multivariate Sensitivity Analysis via Sample Splitting in an Observational Study of the Effects of Poverty on Cardiovascular Disease Risk Factors
University of Pennsylvania（宾夕法尼亚大学）；Emory University School of Medicine（埃默里大学医学院）；University of Michigan（密歇根大学）
We propose a class of two-sample statistics for testing the equality of proportions and the equality of survival functions. We build our proposal on a weighted combination of a score test for the difference in proportions and a Weighted Kaplan-Meier statistic-based test for the difference of survival functions. The proposed statistics are fully non-parametric and do not rely on the proportional hazards assumption for the survival outcome. We present the asymptotic distribution of these statistics, propose a variance estimator and show their asymptotic properties under fixed and local alternati…
Popular guidance on observational data analysis states that outcomes should be blinded when determining matching criteria or propensity scores. Such a blinding is informally said to maintain the "objectivity" of the analysis, and to prevent analysts from fishing for positive results by exploiting chance imbalances. Contrary to this notion, we show that outcome blinding is not a sufficient safeguard against fishing. Blinded and unblinded analysts can produce bias of the same order of magnitude in cases where the outcomes can be approximately predicted from baseline covariates. We illustrate thi…
Mobile sensing data has become a popular data source for geo-spatial analysis, however, mapping it accurately to other sources of information such as statistical data remains a challenge. Popular mapping approaches such as point allocation or voronoi tessellation provide only crude approximations of the mobile network coverage as they do not consider holes, overlaps and within-cell heterogeneity. More elaborate mapping schemes often require additional proprietary data operators are highly reluctant to share. In this paper, I use human settlement information extracted from publicly available sa…
Rapid advancements in collection and dissemination of multi-platform molecular and genomics data has resulted in enormous opportunities to aggregate such data in order to understand, prevent, and treat human diseases. While significant improvements have been made in multi-omic data integration methods to discover biological markers and mechanisms underlying both prognosis and treatment, the precise cellular functions governing these complex mechanisms still need detailed and data-driven de-novo evaluations. We propose a framework called Functional Integrative Bayesian Analysis of High-dimensio…
