This paper addresses patient heterogeneity associated with prediction problems in biomedical applications. We propose a systematic hypothesis testing approach to determine the existence of patient subgroup structure and the number of subgroups in patient population if subgroups exist. A mixture of generalized linear models is considered to model the relationship between the disease outcome and patient characteristics and clinical factors, including targeted biomarker profiles. We construct a test statistic based on expectation maximization (EM) algorithm and derive its asymptotic distribution under the null hypothesis. An important computational advantage of the test is that the involved parameter estimates under the complex alternative hypothesis can be obtained through a small number of EM iterations, rather than optimizing the objective function. We demonstrate the finite sample performance of the proposed test in terms of type-I error rate and power, using extensive simulation studies. The applicability of the proposed method is illustrated through an application to a multi-center prostate cancer study.
An important task in drug development is to identify patients, which respond better or worse to an experimental treatment. Identifying predictive covariates, which influence the treatment effect and can be used to define subgroups of patients, is a key aspect of this task. Analyses of treatment effect heterogeneity are however known to be challenging, since the number of possible covariates or subgroups is often large, while samples sizes in earlier phases of drug development are often small. In addition, distinguishing predictive covariates from prognostic covariates, which influence the resp…
Case-mix heterogeneity across studies complicates meta-analyses. As a result of this, treatments that are equally effective on patient subgroups may appear to have different effectiveness on patient populations with different case mix. It is therefore important that meta-analyses be explicit for what patient population they describe the treatment effect. To achieve this, we develop a new approach for meta-analysis of randomized clinical trials, which use individual patient data (IPD) from all trials to infer the treatment effect for the patient population in a given trial, based on direct stan…
A key challenge in building effective regression models for large and diverse populations is accounting for patient heterogeneity. An example of such heterogeneity is in health system risk modeling efforts where different combinations of comorbidities fundamentally alter the relationship between covariates and health outcomes. Accounting for heterogeneity arising combinations of factors can yield more accurate and interpretable regression models. Yet, in the presence of high dimensional covariates, accounting for this type of heterogeneity can exacerbate estimation difficulties even with large…
Precision medicine is an emerging field that takes into account individual heterogeneity to inform better clinical practice. In clinical trials, the evaluation of treatment effect heterogeneity is an important component, and recently, many statistical methods have been proposed for stratifying patients into different subgroups based on such heterogeneity. However, the majority of existing methods developed for this purpose focus on the case with a dichotomous treatment and are not directly applicable to multi-arm trials. In this paper, we consider the problem of patient stratification in multi…
Unobserved Heterogeneity in Threshold Regression Based on the Hitting Times of a Reflected Brownian Motion for Recurrent Hypoglycemia
Department of Statistics, University of Connecticut（康涅狄格大学统计系）；Department of Biostatistics, Yale School of Public Health（耶鲁公共卫生学院生物统计系）；Indiana University School of Medicine（印第安纳大学医学院）
In electronic health records (EHRs), latent subgroups of patients may exhibit distinctive patterning in their longitudinal health trajectories. For such data, growth mixture models (GMMs) enable classifying patients into different latent classes based on individual trajectories and hypothesized risk factors. However, the application of GMMs is hindered by the special missing data problem in EHRs, which manifests two patient-led missing data processes: the visit process and the response process for an EHR variable conditional on a patient visiting the clinic. If either process is associated wit…
Personalized medicine is the future of medical practice. In oncology, tumor heterogeneity assessment represents a pivotal step for effective treatment planning and prognosis prediction. Despite new procedures for DNA sequencing and analysis, non-invasive methods for tumor characterization are needed to impact on daily routine. On purpose, imaging texture analysis is rapidly scaling, holding the promise to surrogate histopathological assessment of tumor lesions. In this work, we propose a tree-based representation strategy for describing intra-tumor heterogeneity of patients affected by metasta…
In the genomic era, the identification of gene signatures associated with disease is of significant interest. Such signatures are often used to predict clinical outcomes in new patients and aid clinical decision-making. However, recent studies have shown that gene signatures are often not replicable. This occurrence has practical implications regarding the generalizability and clinical applicability of such signatures. To improve replicability, we introduce a novel approach to select gene signatures from multiple datasets whose effects are consistently non-zero and account for between-study he…
Graphical models are commonly used to discover associations within gene or protein networks for complex diseases such as cancer. Most existing methods estimate a single graph for a population, while in many cases, researchers are interested in characterizing the heterogeneity of individual networks across subjects with respect to subject-level covariates. Examples include assessments of how the network varies with patient-specific prognostic scores or comparisons of tumor and normal graphs while accounting for tumor purity as a continuous predictor. In this paper, we propose a novel edge regre…
Empirical prior distributions for treatment-by-subgroup interaction heterogeneity in random-effects meta-analysis
University Medical Center Göttingen（哥廷根大学医学中心）；DZHK (German Center for Cardiovascular Research)（德国心血管研究中心）；DZKJ (German Center for Child and Adolescent Health)（德国儿童与青少年健康中心）
Treatment effect heterogeneity occurs when individual characteristics influence the effect of a treatment. We propose a novel approach that combines prognostic score matching and conditional inference trees to characterize effect heterogeneity of a randomized binary treatment. One key feature that distinguishes our method from alternative approaches is that it controls the Type I error rate, i.e., the probability of identifying effect heterogeneity if none exists and retains the underlying subgroups. This feature makes our technique particularly appealing in the context of clinical trials, whe…
Subgroup analysis is a frequently used tool for evaluating heterogeneity of treatment effect and heterogeneity in treatment harm across observed baseline patient characteristics. While treatment efficacy and adverse event measures are often reported separately for each subgroup, analyzing their within-subgroup joint distribution is critical for better informed patient decision-making. In this paper, we describe Bayesian models for performing a subgroup analysis to compare the joint occurrence of a primary endpoint and an adverse event between two treatment arms. Our approaches emphasize estima…
It is widely acknowledged that the predictive performance of clinical prediction models should be studied in patients that were not part of the data in which the model was derived. Out-of-sample performance can be hampered when predictors are measured differently at derivation and external validation. This may occur, for instance, when predictors are measured using different measurement protocols or when tests are produced by different manufacturers. Although such heterogeneity in predictor measurement between deriviation and validation data is common, the impact on the out-of-sample performan…
The primary benefit of identifying a valid surrogate marker is the ability to use it in a future trial to test for a treatment effect with shorter follow-up time or less cost. However, previous work has demonstrated potential heterogeneity in the utility of a surrogate marker. When such heterogeneity exists, existing methods that use the surrogate to test for a treatment effect while ignoring this heterogeneity may lead to inaccurate conclusions about the treatment effect, particularly when the patient population in the new study has a different mix of characteristics than the study used to ev…
Revealing relationships between genes and disease phenotypes is a critical problem in biomedical studies. This problem has been challenged by the heterogeneity of diseases. Patients of a perceived same disease may form multiple subgroups, and different subgroups have distinct sets of important genes. It is hence imperative to discover the latent subgroups and reveal the subgroup-specific important genes. Some heterogeneity analysis methods have been proposed in recent literature. Despite considerable successes, most of the existing studies are still limited as they cannot accommodate data cont…
An important task in clinical medicine is the construction of risk prediction models for specific subgroups of patients based on high-dimensional molecular measurements such as gene expression data. Major objectives in modeling high-dimensional data are good prediction performance and feature selection to find a subset of predictors that are truly associated with a clinical outcome such as a time-to-event endpoint. In clinical practice, this task is challenging since patient cohorts are typically small and can be heterogeneous with regard to their relationship between predictors and outcome. W…
The objective is to assess the extent of variation of data quality and completeness of electronic health records and impact on the robustness of risk predictions of incident cardiovascular disease (CVD) using a risk prediction tool that is based on routinely collected data (QRISK3). The study design is a longitudinal cohort study with a setting of 392 general practices (including 3.6 million patients) linked to hospital admission data. Variation in data quality was assessed using Saez stability metrics quantifying outlyingness of each practice. Statistical frailty models evaluated whether accu…
