An external control arm is a cohort of control patients that are collected from data external to a single-arm trial. To provide an unbiased estimation of efficacy, the clinical profiles of patients ...from single and external arms should be aligned, typically using propensity score approaches. There are alternative approaches to infer efficacy based on comparisons between outcomes of single-arm patients and machine-learning predictions of control patient outcomes. These methods include G-computation and Doubly Debiased Machine Learning (DDML) and their evaluation for External Control Arms (ECA) analysis is insufficient.
We consider both numerical simulations and a trial replication procedure to evaluate the different statistical approaches: propensity score matching, Inverse Probability of Treatment Weighting (IPTW), G-computation, and DDML. The replication study relies on five type 2 diabetes randomized clinical trials granted by the Yale University Open Data Access (YODA) project. From the pool of five trials, observational experiments are artificially built by replacing a control arm from one trial by an arm originating from another trial and containing similarly-treated patients.
Among the different statistical approaches, numerical simulations show that DDML has the smallest bias followed by G-computation. In terms of mean squared error, G-computation usually minimizes mean squared error. Compared to other methods, DDML has varying Mean Squared Error performances that improves with increasing sample sizes. For hypothesis testing, all methods control type I error and DDML is the most conservative. G-computation is the best method in terms of statistical power, and DDML has comparable power at Formula: see text but inferior ones for smaller sample sizes. The replication procedure also indicates that G-computation minimizes mean squared error whereas DDML has intermediate performances in between G-computation and propensity score approaches. The confidence intervals of G-computation are the narrowest whereas confidence intervals obtained with DDML are the widest for small sample sizes, which confirms its conservative nature.
For external control arm analyses, methods based on outcome prediction models can reduce estimation error and increase statistical power compared to propensity score approaches.
Abstract
Summary
We present PyDESeq2, a python implementation of the DESeq2 workflow for differential expression analysis on bulk RNA-seq data. This re-implementation yields similar, but not ...identical, results: it achieves higher model likelihood, allows speed improvements on large datasets, as shown in experiments on TCGA data, and can be more easily interfaced with modern python-based data science tools.
Availability and Implementation
PyDESeq2 is released as an open-source software under the MIT license. The source code is available on GitHub at https://github.com/owkin/PyDESeq2 and documented at https://pydeseq2.readthedocs.io. PyDESeq2 is part of the scverse ecosystem.
Triple-negative breast cancer (TNBC) is a rare cancer, characterized by high metastatic potential and poor prognosis, and has limited treatment options. The current standard of care in nonmetastatic ...settings is neoadjuvant chemotherapy (NACT), but treatment efficacy varies substantially across patients. This heterogeneity is still poorly understood, partly due to the paucity of curated TNBC data. Here we investigate the use of machine learning (ML) leveraging whole-slide images and clinical information to predict, at diagnosis, the histological response to NACT for early TNBC women patients. To overcome the biases of small-scale studies while respecting data privacy, we conducted a multicentric TNBC study using federated learning, in which patient data remain secured behind hospitals' firewalls. We show that local ML models relying on whole-slide images can predict response to NACT but that collaborative training of ML models further improves performance, on par with the best current approaches in which ML models are trained using time-consuming expert annotations. Our ML model is interpretable and is sensitive to specific histological patterns. This proof of concept study, in which federated learning is applied to real-world datasets, paves the way for future biomarker discovery using unprecedentedly large datasets.
Federated Learning enables one to jointly train a machine learning model across distributed clients holding sensitive datasets. In real-world settings, this approach is hindered by expensive ...communication and privacy concerns. Both of these challenges have already been addressed individually, resulting in competing optimisations. In this article, we tackle them simultaneously for one of the first times. More precisely, we adapt compression-based federated techniques to additive secret sharing, leading to an efficient secure aggregation protocol, with an adaptable security level. We prove its privacy against malicious adversaries and its correctness in the semi-honest setting. Experiments on deep convolutional networks demonstrate that our secure protocol achieves high accuracy with low communication costs. Compared to prior works on secure aggregation, our protocol has a lower communication and computation costs for a similar accuracy.
The Yeo-Johnson (YJ) transformation is a standard parametrized per-feature unidimensional transformation often used to Gaussianize features in machine learning. In this paper, we investigate the ...problem of applying the YJ transformation in a cross-silo Federated Learning setting under privacy constraints. For the first time, we prove that the YJ negative log-likelihood is in fact convex, which allows us to optimize it with exponential search. We numerically show that the resulting algorithm is more stable than the state-of-the-art approach based on the Brent minimization method. Building on this simple algorithm and Secure Multiparty Computation routines, we propose SecureFedYJ, a federated algorithm that performs a pooled-equivalent YJ transformation without leaking more information than the final fitted parameters do. Quantitative experiments on real data demonstrate that, in addition to being secure, our approach reliably normalizes features across silos as well as if data were pooled, making it a viable approach for safe federated feature Gaussianization.
External control arms (ECA) can inform the early clinical development of experimental drugs and provide efficacy evidence for regulatory approval in non-randomized settings. However, the main ...challenge of implementing ECA lies in accessing real-world data or historical clinical trials. Indeed, data sharing is often not feasible due to privacy considerations related to data leaving the original collection centers, along with pharmaceutical companies' competitive motives. In this paper, we leverage a privacy-enhancing technology called federated learning (FL) to remove some of the barriers to data sharing. We introduce a federated learning inverse probability of treatment weighted (IPTW) method for time-to-event outcomes called FedECA which eases the implementation of ECA by limiting patients' data exposure. We show with extensive experiments that FedECA outperforms its closest competitor, matching-adjusted indirect comparison (MAIC), in terms of statistical power and ability to balance the treatment and control groups. To encourage the use of such methods, we publicly release our code which relies on Substra, an open-source FL software with proven experience in privacy-sensitive contexts.
While federated learning is a promising approach for training deep learning models over distributed sensitive datasets, it presents new challenges for machine learning, especially when applied in the ...medical domain where multi-centric data heterogeneity is common. Building on previous domain adaptation works, this paper proposes a novel federated learning approach for deep learning architectures via the introduction of local-statistic batch normalization (BN) layers, resulting in collaboratively-trained, yet center-specific models. This strategy improves robustness to data heterogeneity while also reducing the potential for information leaks by not sharing the center-specific layer activation statistics. We benchmark the proposed method on the classification of tumorous histopathology image patches extracted from the Camelyon16 and Camelyon17 datasets. We show that our approach compares favorably to previous state-of-the-art methods, especially for transfer learning across datasets.
Building machine learning models from decentralized datasets located in different centers with federated learning (FL) is a promising approach to circumvent local data scarcity while preserving ...privacy. However, the prominent Cox proportional hazards (PH) model, used for survival analysis, does not fit the FL framework, as its loss function is non-separable with respect to the samples. The na\"ive method to bypass this non-separability consists in calculating the losses per center, and minimizing their sum as an approximation of the true loss. We show that the resulting model may suffer from important performance loss in some adverse settings. Instead, we leverage the discrete-time extension of the Cox PH model to formulate survival analysis as a classification problem with a separable loss function. Using this approach, we train survival models using standard FL techniques on synthetic data, as well as real-world datasets from The Cancer Genome Atlas (TCGA), showing similar performance to a Cox PH model trained on aggregated data. Compared to previous works, the proposed method is more communication-efficient, more generic, and more amenable to using privacy-preserving techniques.
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