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      DeepSurv: personalized treatment recommender system using a Cox proportional hazards deep neural network

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          Abstract

          Background

          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 systems.

          Methods

          We introduce DeepSurv, a Cox proportional hazards deep neural network and state-of-the-art survival method for modeling interactions between a patient’s covariates and treatment effectiveness in order to provide personalized treatment recommendations.

          Results

          We perform a number of experiments training DeepSurv on simulated and real survival data. We demonstrate that DeepSurv performs as well as or better than other state-of-the-art survival models and validate that DeepSurv successfully models increasingly complex relationships between a patient’s covariates and their risk of failure. We then show how DeepSurv models the relationship between a patient’s features and effectiveness of different treatment options to show how DeepSurv can be used to provide individual treatment recommendations. Finally, we train DeepSurv on real clinical studies to demonstrate how it’s personalized treatment recommendations would increase the survival time of a set of patients.

          Conclusions

          The predictive and modeling capabilities of DeepSurv will enable medical researchers to use deep neural networks as a tool in their exploration, understanding, and prediction of the effects of a patient’s characteristics on their risk of failure.

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          Most cited references37

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          An Introduction to the Bootstrap

          Statistics is a subject of many uses and surprisingly few effective practitioners. The traditional road to statistical knowledge is blocked, for most, by a formidable wall of mathematics. The approach in An Introduction to the Bootstrap avoids that wall. It arms scientists and engineers, as well as statisticians, with the computational techniques they need to analyze and understand complicated data sets.
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            The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

            The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.
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              Modeling Survival Data: Extending the Cox Model

              This is a book for statistical practitioners, particularly those who design and analyze studies for survival and event history data. Its goal is to extend the toolkit beyond the basic triad provided by most statistical packages: the Kaplan-Meier estimator, log-rank test, and Cox regression model. Building on recent developments motivated by counting process and martingale theory, it shows the reader how to extend the Cox model to analyse multiple/correlated event data using marginal and random effects (frailty) models. It covers the use of residuals and diagnostic plots to identify influential or outlying observations, assess proportional hazards and examine other aspects of goodness of fit. Other topics include time-dependent covariates and strata, discontinuous intervals of risk, multiple time scales, smoothing and regression splines, and the computation of expected survival curves. A knowledge of counting processes and martingales is not assumed as the early chapters provide an introduction to this area. The focus of the book is on actual data examples, the analysis and interpretation of the results, and computation. The methods are now readily available in SAS and S-Plus and this book gives a hands-on introduction, showing how to implement them in both packages, with worked examples for many data sets. The authors call on their extensive experience and give practical advice, including pitfalls to be avoided. Terry Therneau is Head of the Section of Biostatistics, Mayo Clinic, Rochester, Minnesota. He is actively involved in medical consulting, with emphasis in the areas of chronic liver disease, physical medicine, hematology, and laboratory medicine, and is an author on numerous papers in medical and statistical journals. He wrote two of the original SAS procedures for survival analysis (coxregr and survtest), as well as the majority of the S-Plus survival functions. Patricia Grambsch is Associate Professor in the Division of Biostatistics, School of Public Health, University of Minnesota. She has collaborated extensively with physicians and public health researchers in chronic liver disease, cancer prevention, hypertension clinical trials and psychiatric research. She is a fellow the American Statistical Association and the author of many papers in medical and statistical journals.
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                Author and article information

                Contributors
                jared.katzman@aya.yale.edu
                uri.shaham@yale.edu
                yuval.kluger@yale.edu
                Journal
                BMC Med Res Methodol
                BMC Med Res Methodol
                BMC Medical Research Methodology
                BioMed Central (London )
                1471-2288
                26 February 2018
                26 February 2018
                2018
                : 18
                : 24
                Affiliations
                [1 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Computer Science, , Yale University, ; 51 Prospect Street, New Haven, 06511 CT USA
                [2 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Statistics, , Yale University, ; 24 Hillhouse Avenue, New Haven, 06511 CT USA
                [3 ]ISNI 0000000419368710, GRID grid.47100.32, Applied Mathematics Program, Yale University, ; 51 Prospect Street, New Haven, 06511 CT USA
                [4 ]ISNI 0000000419368710, GRID grid.47100.32, Yale School of Medicine, ; 333 Cedar Street, New Haven, 06510 CT USA
                [5 ]GRID grid.417307.6, Center of Outcomes Research and Evaluation, Yale-New Haven Hospital, ; New Haven, 06511 CT USA
                [6 ]ISNI 0000000419368710, GRID grid.47100.32, Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, ; New Haven, 06511 CT USA
                [7 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Pathology and Yale Cancer Center, , Yale University School of Medicine, ; New Haven, 06511 CT USA
                [8 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Mathematics, , University of California, San Diego, ; La Jolla, 92093 CA USA
                [9 ]Final Research, Herzliya, Israel
                Author information
                http://orcid.org/0000-0002-3035-071X
                Article
                482
                10.1186/s12874-018-0482-1
                5828433
                29482517
                c2282a54-c09f-48a6-8c79-3f0e479abcd6
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 3 September 2017
                : 7 February 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000051, National Human Genome Research Institute;
                Award ID: 1R01HG008383-01A1
                Funded by: FundRef http://dx.doi.org/10.13039/100000086, Directorate for Mathematical and Physical Sciences;
                Award ID: DMS-1402254
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Medicine
                deep learning,survival analysis,treatment recommendations
                Medicine
                deep learning, survival analysis, treatment recommendations

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