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. When data of several subgroups of patients with the same or similar disease are available, it is tempting to combine them to increase sample size, such as in multicenter studies. However, heterogeneity between subgroups can lead to biased results and subgroup-specific effects may remain undetected. For this situation, we propose a penalized Cox regression model with a weighted version of the Cox partial likelihood that includes patients of all subgroups but assigns them individual weights based on their subgroup affiliation. Patients who are likely to belong to the subgroup of interest obtain higher weights in the subgroup-specific model. Our proposed approach is evaluated through simulations and application to real lung cancer cohorts. Simulation results demonstrate that our model can achieve improved prediction and variable selection accuracy over standard approaches.
Combining patient-level data from clinical trials can connect rare phenomena with clinical endpoints, but statistical techniques applied to a single trial may become problematical when trials are pooled. Estimating the hazard of a binary variable unevenly distributed across trials showcases a common pooled database issue. We studied how an unevenly distributed binary variable can compromise the integrity of fixed and random effects Cox proportional hazards models. We compared fixed effect and random effects Cox proportional hazards models on a set of simulated datasets inspired by a 17-trial p…
University Paris Descartes（巴黎笛卡尔大学）；Institut Hypercube（超立方体研究所）；Montreal Institute for Learning Algorithms（蒙特利尔学习算法研究所）；École Polytechnique de Montréal（蒙特利尔理工学院）
An accurate model of patient-specific kidney graft survival distributions can help to improve shared-decision making in the treatment and care of patients. In this paper, we propose a deep learning method that directly models the survival function instead of estimating the hazard function to predict survival times for graft patients based on the principle of multi-task learning. By learning to jointly predict the time of the event, and its rank in the cox partial log likelihood framework, our deep learning approach outperforms, in terms of survival time prediction quality and concordance index…
Odense University Hospital（欧登塞大学医院）；University of Southern Denmark（南丹麦大学）；UNSW（新南威尔士大学）；Ingham Institute for Applied Medical Research（英厄姆应用医学研究所）；The University of Manchester（曼彻斯特大学）；Manchester Academic Health Science Centre（曼彻斯特学术健康科学中心）；The Christie NHS Foundation Trust（克里斯蒂国民保健服务基金会信托）；University of Sydney（悉尼大学）；Liverpool and Macarthur Cancer Therapy Centres（利物浦和麦克阿瑟癌症治疗中心）
Medical data are often highly sensitive, and frequently there are missing data. Due to the data's sensitive nature, there is an interest in creating modelling methods where the data are kept in each local centre to preserve their privacy, but yet the model can be trained on and learn from data across multiple centres. Such an approach might be distributed machine learning (federated learning, collaborative learning) in which a model is iteratively calculated based on aggregated local model information from each centre. However, even though no specific data are leaving the centre, there is a po…
Analysing subgroups defined by biomarkers is of increasing importance in clinical research. In some situations the biomarker is subject to misclassification error, meaning the true subgroups are identified with imperfect sensitivity and specificity. For time-to-event data, it is improper to assume the Cox proportional hazards model for the effects with respect to the true subgroups, since the survival distributions with respect to the diagnosed subgroups will not adhere to the proportional hazards assumption. This precludes the possibility of using simple adjustment procedures. Instead, we pre…
Medical practitioners use survival models to explore and understand the relationships between patients' covariates (e.g. clinical and genetic features) and the effectiveness of various treatment options. Standard survival models like the linear Cox proportional hazards model require extensive feature engineering or prior medical knowledge to model treatment interaction at an individual level. While nonlinear survival methods, such as neural networks and survival forests, can inherently model these high-level interaction terms, they have yet to be shown as effective treatment recommender system…
What Risk Factors to Cause Long COVID and Its Impact on Patient Survival Outcomes when Combined with the Effect from Organ Transplantation in the Acute COVID
Penalized Deep Partially Linear Cox Models with Application to CT Scans of Lung Cancer Patients
William & Mary（威廉与玛丽学院）；University of Michigan（密歇根大学）；Massachusetts General Hospital（麻省总医院）；Duke University（杜克大学）；Harvard T.H. Chan School of Public Health（哈佛大学陈曾熙公共卫生学院）
Comparison of the Cox proportional hazards model and Random Survival Forest algorithm for predicting patient-specific survival probabilities in clinical trial data
University of Augsburg（奥格斯堡大学）；University of Reading（雷丁大学）
Machine learning has become ubiquitous and a key technology on mining electronic health records (EHRs) for facilitating clinical research and practice. Unsupervised machine learning, as opposed to supervised learning, has shown promise in identifying novel patterns and relations from EHRs without using human created labels. In this paper, we investigate the application of unsupervised machine learning models in discovering latent disease clusters and patient subgroups based on EHRs. We utilized Latent Dirichlet Allocation (LDA), a generative probabilistic model, and proposed a novel model name…
Most prediction models that are used in medical research fail to accurately predict health outcomes due to methodological limitations. Using routinely collected patient data, we explore the use of a Cox proportional hazard (PH) model within a latent class framework to model survival of patients with chronic heart failure (CHF). We identify subgroups of patients based on their risk with the aid of available covariates. We allow each subgroup to have its own risk model.We choose an optimum number of classes based on the reported Bayesian information criteria (BIC). We assess the discriminative a…
Important objectives in cancer research are the prediction of a patient's risk based on molecular measurements such as gene expression data and the identification of new prognostic biomarkers (e.g. genes). In clinical practice, this is often challenging because patient cohorts are typically small and can be heterogeneous. In classical subgroup analysis, a separate prediction model is fitted using only the data of one specific cohort. However, this can lead to a loss of power when the sample size is small. Simple pooling of all cohorts, on the other hand, can lead to biased results, especially …
This paper presents an original approach for jointly fitting survival times and classifying samples into subgroups. The Coxlogit model is a generalized linear model with a common set of selected features for both tasks. Survival times and class labels are here assumed to be conditioned by a common risk score which depends on those features. Learning is then naturally expressed as maximizing the joint probability of subgroup labels and the ordering of survival events, conditioned to a common weight vector. The model is estimated by minimizing a regularized log-likelihood through a coordinate de…
Data-driven subgrouping of patient trajectories with chronic diseases: Evidence from low back pain
ETH Zurich（苏黎世联邦理工学院）；University of Southern Denmark（南丹麦大学）；Chiropractic Knowledge Hub（脊椎指压治疗知识中心）；Basel Academy for Quality and Research in Medicine（巴塞尔医学质量与研究学院）；University of Basel（巴塞尔大学）；LMU Munich（慕尼黑大学）；Munich Center for Machine Learning（慕尼黑机器学习中心）
The identification of patient subgroups with differential treatment effects is the first step towards individualised treatments. A current draft guideline by the EMA discusses potentials and problems in subgroup analyses and formulated challenges to the development of appropriate statistical procedures for the data-driven identification of patient subgroups. We introduce model-based recursive partitioning as a procedure for the automated detection of patient subgroups that are identifiable by predictive factors. The method starts with a model for the overall treatment effect as defined for the…
Pharmaceutical companies continue to seek innovative ways to explore whether a drug under development is likely to be suitable for all or only an identifiable stratum of patients in the target population. The sooner this can be done during the clinical development process, the better it is for the company, and downstream for prescribers, payers, and most importantly, for patients. To help enable this vision of stratified medicine, we describe a powerful statistical framework, Patient Response Identifiers for Stratified Medicine (PRISM), for the discovery of potential predictors of drug respons…
An important task in early phase drug development is to identify patients, which respond better or worse to an experimental treatment. While a variety of different subgroup identification methods have been developed for the situation of trials that study an experimental treatment and control, much less work has been done in the situation when patients are randomized to different dose groups. In this article we propose new strategies to perform subgroup analyses in dose-finding trials and discuss the challenges, which arise in this new setting. We consider model-based recursive partitioning, wh…
