Exploratory cancer drug studies test multiple tumor cell lines against multiple candidate drugs. The goal in each paired (cell line, drug) experiment is to map out the dose-response curve of the cell line as the dose level of the drug increases. We propose Bayesian Tensor Filtering (BTF), a hierarchical Bayesian model for dose-response modeling in multi-sample, multi-treatment cancer drug studies. BTF uses low-dimensional embeddings to share statistical strength between similar drugs and similar cell lines. Structured shrinkage priors in BTF encourage smoothness in the dose-response curves while remaining adaptive to sharp jumps when the data call for it. We focus on a pair of cancer drug studies exhibiting a particular pathology in their experimental design, leading us to a non-conjugate monotone mixture-of-Gammas likelihood. To perform posterior inference, we develop a variant of the elliptical slice sampling algorithm for sampling from linearly-constrained multivariate normal priors with non-conjugate likelihoods. In benchmarks, BTF outperforms state-of-the-art methods for covariance regression and dynamic Poisson matrix factorization. On the two cancer drug studies, BTF outperforms the current standard approach in biology and reveals potential new biomarkers of drug sensitivity in cancer. Code is available at https://github.com/tansey/functionalmf.
Drug combination trials are increasingly common nowadays in clinical research. However, very few methods have been developed to consider toxicity attributions in the dose escalation process. We are motivated by a trial in which the clinician is able to identify certain toxicities that can be attributed to one of the agents. We present a Bayesian adaptive design in which toxicity attributions are modeled via Copula regression and the maximum tolerated dose (MTD) curve is estimated as a function of model parameters. The dose escalation algorithm uses cohorts of two patients, following the contin…
In Oncology, trials evaluating drug combinations are becoming more common. While combination therapies bring the potential for greater efficacy, they also create unique challenges for ensuring drug safety. In Phase-I dose escalation trials of drug combinations, model-based approaches enable efficient use of information gathered, but the models need to account for trial complexities: appropriate modeling of interactions becomes increasingly important with growing numbers of drugs being tested simultaneously in a given trial. In principle, we can use data from multiple arms testing varying combi…
The use of drug combinations in clinical trials is increasingly common during the last years since a more favorable therapeutic response may be obtained by combining drugs. In phase I clinical trials, most of the existing methodology recommends a one unique dose combination as "optimal", which may result in a subsequent failed phase II clinical trial since other dose combinations may present higher treatment efficacy for the same level of toxicity. We are particularly interested in the setting where it is necessary to wait a few cycles of therapy to observe an efficacy outcome and the phase I …
Enhancing drug and cell line representations via contrastive learning for improved anti-cancer drug prioritization
The Ohio State University（俄亥俄州立大学）；Biomedical Informatics Department, The Ohio State University（俄亥俄州立大学生物医学信息学系）；Computer Science and Engineering Department, The Ohio State University（俄亥俄州立大学计算机科学与工程系）；Translational Data Analytics Institute, The Ohio State University（俄亥俄州立大学转化数据分析研究所）
We propose an adaptive design for early phase drug combination cancer trials with the goal of estimating the maximum tolerated dose (MTD). A nonparametric Bayesian model, using beta priors truncated to the set of partially ordered dose combinations, is used to describe the probability of dose limiting toxicity (DLT). Dose allocation between successive cohorts of patients is estimated using a modified Continual Reassessment scheme. The updated probabilities of DLT are calculated with a Gibbs sampler that employs a weighting mechanism to calibrate the influence of data versus the prior. At the e…
Permutation invariant multi-output Gaussian Processes for drug combination prediction in cancer
MRC Biostatistics Unit, University of Cambridge（剑桥大学医学研究委员会生物统计学单元）；Oslo Centre for Biostatistics and Epidemiology (OCBE), University of Oslo（奥斯陆大学奥斯陆生物统计学与流行病学中心）；Broad Institute of MIT & Harvard（麻省理工学院与哈佛大学博德研究所）；CRUK Cambridge Centre Ovarian Programme（英国癌症研究剑桥中心卵巢项目）；Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID)（剑桥治疗免疫学与传染病研究所）
Phase I dose-finding trials in oncology seek to find the maximum tolerated dose (MTD) of a drug under a specific schedule. Evaluating drug-schedules aims at improving treatment safety while maintaining efficacy. However, while we can reasonably assume that toxicity increases with the dose for cytotoxic drugs, the relationship between toxicity and multiple schedules remains elusive. We proposed a Bayesian dose-regimen assessment method (DRtox) using pharmacokinetics/pharmacodynamics (PK/PD) information to estimate the maximum tolerated dose-regimen (MTD-regimen), at the end of the dose-escalati…
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 to 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 drug…
Institute of Molecular Systems Biology, ETH Zürich（苏黎世联邦理工学院分子系统生物学研究所）
In this work, we propose two novel methodologies to study temporal and morphological phenotypic effects caused by different experimental conditions using imaging data. As a proof of concept, we apply them to analyze drug effects in 2D cancer cell cultures. We train a convolutional autoencoder on 1M images dataset with random augmentations and multi-crops to use as feature extractor. We systematically compare it to the pretrained state-of-the-art models. We further use the feature extractor in two ways. First, we apply distance-based analysis and dynamic time warping to cluster temporal pattern…
PKComb-BOIN12: A Pharmacokinetically Guided Bayesian Design for Dose Optimisation in Oncology Drug-Combination Trials
Global Statistical Sciences, Eli Lilly and Company（礼来公司全球统计科学部）；Department of Biostatistics, The University of Texas MD Anderson Cancer Center（德克萨斯大学安德森癌症中心生物统计学系）；Population Health Sciences Institute, Newcastle University（纽卡斯尔大学人口健康科学研究所）
We propose a new integrated phase I/II trial design to identify the most efficacious dose combination that also satisfies certain safety requirements for drug-combination trials. We first take a Bayesian copula-type model for dose finding in phase I. After identifying a set of admissible doses, we immediately move the entire set forward to phase II. We propose a novel adaptive randomization scheme to favor assigning patients to more efficacious dose-combination arms. Our adaptive randomization scheme takes into account both the point estimate and variability of efficacy. By using a moving refe…
Sejong University（世宗大学）；University of Virginia（弗吉尼亚大学）；UCLA（加州大学洛杉矶分校）；Yonsei University（延世大学）；University of Cambridge（剑桥大学）；The Alan Turing Institute（艾伦·图灵研究所）
Phase I clinical trials are designed to test the safety (non-toxicity) of drugs and find the maximum tolerated dose (MTD). This task becomes significantly more challenging when multiple-drug dose-combinations (DC) are involved, due to the inherent conflict between the exponentially increasing DC candidates and the limited patient budget. This paper proposes a novel Bayesian design, SDF-Bayes, for finding the MTD for drug combinations in the presence of safety constraints. Rather than the conventional principle of escalating or de-escalating the current dose of one drug (perhaps alternating bet…
Harbin Institute of Technology at Weihai（哈尔滨工业大学（威海））；University of Edinburgh（爱丁堡大学）；Sun Yat-sen University（中山大学）；University of Arizona（亚利桑那大学）
Cancer is a primary cause of human death, but discovering drugs and tailoring cancer therapies are expensive and time-consuming. We seek to facilitate the discovery of new drugs and treatment strategies for cancer using variational autoencoders (VAEs) and multi-layer perceptrons (MLPs) to predict anti-cancer drug responses. Our model takes as input gene expression data of cancer cell lines and anti-cancer drug molecular data and encodes these data with our {\sc {GeneVae}} model, which is an ordinary VAE model, and a rectified junction tree variational autoencoder ({\sc JTVae}) model, respectiv…
Dose-finding design based on level set estimation in phase I cancer clinical trials
Nagoya University（名古屋大学）；Kyoto University（京都大学）；MI-6 Ltd.（MI-6有限公司）；Nagoya Institute of Technology（名古屋工业大学）；The Institute of Statistical Mathematics（统计数学研究所）
King Abdulaziz University（阿卜杜勒阿齐兹国王大学）；New Jersey Institute of Technology（新泽西理工学院）
Accurately predicting drug responses to cancer is an important problem hindering oncologists' efforts to find the most effective drugs to treat cancer, which is a core goal in precision medicine. The scientific community has focused on improving this prediction based on genomic, epigenomic, and proteomic datasets measured in human cancer cell lines. Real-world cancer cell lines contain noise, which degrades the performance of machine learning algorithms. This problem is rarely addressed in the existing approaches. In this paper, we present a noise-filtering approach that integrates techniques …
IBM Research（IBM研究院）；University of Melbourne（墨尔本大学）；Cures Within Reach for Cancer（癌症可及疗法组织）；Massachusetts Institute of Technology（麻省理工学院）；Harvard Medical School（哈佛医学院）
More than 200 generic drugs approved by the U.S. Food and Drug Administration for non-cancer indications have shown promise for treating cancer. Due to their long history of safe patient use, low cost, and widespread availability, repurposing of generic drugs represents a major opportunity to rapidly improve outcomes for cancer patients and reduce healthcare costs worldwide. Evidence on the efficacy of non-cancer generic drugs being tested for cancer exists in scientific publications, but trying to manually identify and extract such evidence is intractable. In this paper, we introduce a system…
IBM Research – Zurich（IBM苏黎世研究院）；Institute für Molekulare Systembiologie（分子系统生物学研究所）
We present the Network-based Biased Tree Ensembles (NetBiTE) method for drug sensitivity prediction and drug sensitivity biomarker identification in cancer using a combination of prior knowledge and gene expression data. Our devised method consists of a biased tree ensemble that is built according to a probabilistic bias weight distribution. The bias weight distribution is obtained from the assignment of high weights to the drug targets and propagating the assigned weights over a protein-protein interaction network such as STRING. The propagation of weights, defines neighborhoods of influence …
Washington University School of Medicine, Washington University in St. Louis（圣路易斯华盛顿大学医学院）；Dalian University of Technology（大连理工大学）
Drug resistance is still a major challenge in cancer therapy. Drug combination is expected to overcome drug resistance. However, the number of possible drug combinations is enormous, and thus it is infeasible to experimentally screen all effective drug combinations considering the limited resources. Therefore, computational models to predict and prioritize effective drug combinations is important for combinatory therapy discovery in cancer. In this study, we proposed a novel deep learning model, AuDNNsynergy, to prediction drug combinations by integrating multi-omics data and chemical structur…
Drug Selection via Joint Push and Learning to Rank
Georgia Institute of Technology（佐治亚理工学院）；Twentieth Century Fox（二十世纪福克斯公司）；Starfleet Academy（星际舰队学院）；Indiana University - Purdue University Indianapolis（印第安纳大学-普渡大学印第安纳波利斯分校）
TOBB University of Economics and Technology（TOBB经济与技术大学）；Hacettepe University（哈塞特佩大学）
Chemotherapeutic response of cancer cells to a given compound is one of the most fundamental information one requires to design anti-cancer drugs. Recent advances in producing large drug screens against cancer cell lines provided an opportunity to apply machine learning methods for this purpose. In addition to cytotoxicity databases, considerable amount of drug-induced gene expression data has also become publicly available. Following this, several methods that exploit omics data were proposed to predict drug activity on cancer cells. However, due to the complexity of cancer drug mechanisms, n…
Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio（德克萨斯大学圣安东尼奥健康科学中心格里希儿童癌症研究所）；University of Texas at San Antonio（德克萨斯大学圣安东尼奥分校）；Northwestern Polytechnical University（西北工业大学）；Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio（德克萨斯大学圣安东尼奥健康科学中心流行病学与生物统计学系）
The study of high-throughput genomic profiles from a pharmacogenomics viewpoint has provided unprecedented insights into the oncogenic features modulating drug response. A recent screening of ~1,000 cancer cell lines to a collection of anti-cancer drugs illuminated the link between genotypes and vulnerability. However, due to essential differences between cell lines and tumors, the translation into predicting drug response in tumors remains challenging. Here we proposed a DNN model to predict drug response based on mutation and expression profiles of a cancer cell or a tumor. The model contain…
SDIVF R&D Centre（SDIVF研发中心）；The Chinese University of Hong Kong（香港中文大学）
Understanding the phenotypic drug response on cancer cell lines plays a vital rule in anti-cancer drug discovery and re-purposing. The Genomics of Drug Sensitivity in Cancer (GDSC) database provides open data for researchers in phenotypic screening to test their models and methods. Previously, most research in these areas starts from the fingerprints or features of drugs, instead of their structures. In this paper, we introduce a model for phenotypic screening, which is called twin Convolutional Neural Network for drugs in SMILES format (tCNNS). tCNNS is comprised of CNN input channels for dru…
Texas Tech University（德克萨斯理工大学）；University of Nebraska-Lincoln（内布拉斯加大学林肯分校）
Anti-cancer drug sensitivity prediction using deep learning models for individual cell line is a significant challenge in personalized medicine. REFINED (REpresentation of Features as Images with NEighborhood Dependencies) CNN (Convolutional Neural Network) based models have shown promising results in drug sensitivity prediction. The primary idea behind REFINED CNN is representing high dimensional vectors as compact images with spatial correlations that can benefit from convolutional neural network architectures. However, the mapping from a vector to a compact 2D image is not unique due to var…
Centrum Wiskunde & Informatica（数学与计算机科学中心）；Utrecht University（乌得勒支大学）；Massachusetts General Hospital（麻省总医院）；Harvard Medical School（哈佛医学院）；Maastricht University Medical Centre+（马斯特里赫特大学医学中心+）
Personalizing drug prescriptions in cancer care based on genomic information requires associating genomic markers with treatment effects. This is an unsolved challenge requiring genomic patient data in yet unavailable volumes as well as appropriate quantitative methods. We attempt to solve this challenge for an experimental proxy for which sufficient data is available: 42 drugs tested on 1018 cancer cell lines. Our goal is to develop a method to identify the drug that is most promising based on a cell line's genomic information. For this, we need to identify for each drug the machine learning …
University of Cambridge（剑桥大学）；Yonsei University（延世大学）；University of Virginia（弗吉尼亚大学）；University of Oxford（牛津大学）；UCLA（加利福尼亚大学洛杉矶分校）
Clinical trials in the medical domain are constrained by budgets. The number of patients that can be recruited is therefore limited. When a patient population is heterogeneous, this creates difficulties in learning subgroup specific responses to a particular drug and especially for a variety of dosages. In addition, patient recruitment can be difficult by the fact that clinical trials do not aim to provide a benefit to any given patient in the trial. In this paper, we propose C3T-Budget, a contextual constrained clinical trial algorithm for dose-finding under both budget and safety constraints…
Motivation: Analysis of relationships of drug structure to biological response is key to understanding off-target and unexpected drug effects, and for developing hypotheses on how to tailor drug thera-pies. New methods are required for integrated analyses of a large number of chemical features of drugs against the corresponding genome-wide responses of multiple cell models. Results: In this paper, we present the first comprehensive multi-set analysis on how the chemical structure of drugs impacts on ge-nome-wide gene expression across several cancer cell lines (CMap database). The task is form…
