Precision medicine for chronic diseases such as multiple sclerosis (MS) involves choosing a treatment which best balances efficacy and side effects/preferences for individual patients. Making this choice as early as possible is important, as delays in finding an effective therapy can lead to irreversible disability accrual. To this end, we present the first deep neural network model for individualized treatment decisions from baseline magnetic resonance imaging (MRI) (with clinical information if available) for MS patients. Our model (a) predicts future new and enlarging T2 weighted (NE-T2) lesion counts on follow-up MRI on multiple treatments and (b) estimates the conditional average treatment effect (CATE), as defined by the predicted future suppression of NE-T2 lesions, between different treatment options relative to placebo. Our model is validated on a proprietary federated dataset of 1817 multi-sequence MRIs acquired from MS patients during four multi-centre randomized clinical trials. Our framework achieves high average precision in the binarized regression of future NE-T2 lesions on five different treatments, identifies heterogeneous treatment effects, and provides a personalized treatment recommendation that accounts for treatment-associated risk (e.g. side effects, patient preference, administration difficulties).
Many automatic machine learning models developed for focal pathology (e.g. lesions, tumours) detection and segmentation perform well, but do not generalize as well to new patient cohorts, impeding their widespread adoption into real clinical contexts. One strategy to create a more diverse, generalizable training set is to naively pool datasets from different cohorts. Surprisingly, training on this \it{big data} does not necessarily increase, and may even reduce, overall performance and model generalizability, due to the existence of cohort biases that affect label distributions. In this paper, we propose a generalized affine conditioning framework to learn and account for cohort biases across multi-source datasets, which we call Source-Conditioned Instance Normalization (SCIN). Through extensive experimentation on three different, large scale, multi-scanner, multi-centre Multiple Sclerosis (MS) clinical trial MRI datasets, we show that our cohort bias adaptation method (1) improves performance of the network on pooled datasets relative to naively pooling datasets and (2) can quickly adapt to a new cohort by fine-tuning the instance normalization parameters, thus learning the new cohort bias with only 10 labelled samples.
There are many clinical contexts which require accurate detection and segmentation of all focal pathologies (e.g. lesions, tumours) in patient images. In cases where there are a mix of small and large lesions, standard binary cross entropy loss will result in better segmentation of large lesions at the expense of missing small ones. Adjusting the operating point to accurately detect all lesions generally leads to oversegmentation of large lesions. In this work, we propose a novel reweighing strategy to eliminate this performance gap, increasing small pathology detection performance while maintaining segmentation accuracy. We show that our reweighing strategy vastly outperforms competing strategies based on experiments on a large scale, multi-scanner, multi-center dataset of Multiple Sclerosis patient images.
Segmentation of enhancing tumours or lesions from MRI is important for detecting new disease activity in many clinical contexts. However, accurate segmentation requires the inclusion of medical images (e.g., T1 post contrast MRI) acquired after injecting patients with a contrast agent (e.g., Gadolinium), a process no longer thought to be safe. Although a number of modality-agnostic segmentation networks have been developed over the past few years, they have been met with limited success in the context of enhancing pathology segmentation. In this work, we present HAD-Net, a novel offline adversarial knowledge distillation (KD) technique, whereby a pre-trained teacher segmentation network, with access to all MRI sequences, teaches a student network, via hierarchical adversarial training, to better overcome the large domain shift presented when crucial images are absent during inference. In particular, we apply HAD-Net to the challenging task of enhancing tumour segmentation when access to post-contrast imaging is not available. The proposed network is trained and tested on the BraTS 2019 brain tumour segmentation challenge dataset, where it achieves performance improvements in the ranges of 16% - 26% over (a) recent modality-agnostic segmentation methods (U-HeMIS, U-HVED), (b) KD-Net adapted to this problem, (c) the pre-trained student network and (d) a non-hierarchical version of the network (AD-Net), in terms of Dice scores for enhancing tumour (ET). The network also shows improvements in tumour core (TC) Dice scores. Finally, the network outperforms both the baseline student network and AD-Net in terms of uncertainty quantification for enhancing tumour segmentation based on the BraTs 2019 uncertainty challenge metrics. Our code is publicly available at: https://github.com/SaverioVad/HAD_Net
Strong empirical evidence that one machine-learning algorithm A outperforms another one B ideally calls for multiple trials optimizing the learning pipeline over sources of variation such as data sampling, data augmentation, parameter initialization, and hyperparameters choices. This is prohibitively expensive, and corners are cut to reach conclusions. We model the whole benchmarking process, revealing that variance due to data sampling, parameter initialization and hyperparameter choice impact markedly the results. We analyze the predominant comparison methods used today in the light of this variance. We show a counter-intuitive result that adding more sources of variation to an imperfect estimator approaches better the ideal estimator at a 51 times reduction in compute cost. Building on these results, we study the error rate of detecting improvements, on five different deep-learning tasks/architectures. This study leads us to propose recommendations for performance comparisons.