Conformal Drug Property Prediction with Density Estimation under Covariate Shift

In drug discovery, it is vital to confirm the predictions of pharmaceutical properties from computational models using costly wet-lab experiments. Hence, obtaining reliable uncertainty estimates is crucial for prioritizing drug molecules for subsequent experimental validation. Conformal Prediction (CP) is a promising tool for creating such prediction sets for molecular properties with a coverage guarantee. However, the exchangeability assumption of CP is often challenged with covariate shift in drug discovery tasks: Most datasets contain limited labeled data, which may not be representative of the vast chemical space from which molecules are drawn. To address this limitation, we propose a method called CoDrug that employs an energy-based model leveraging both training data and unlabelled data, and Kernel Density Estimation (KDE) to assess the densities of a molecule set. The estimated densities are then used to weigh the molecule samples while building prediction sets and rectifying for distribution shift. In extensive experiments involving realistic distribution drifts in various small-molecule drug discovery tasks, we demonstrate the ability of CoDrug to provide valid prediction sets and its utility in addressing the distribution shift arising from de novo drug design models. On average, using CoDrug can reduce the coverage gap by over 35% when compared to conformal prediction sets not adjusted for covariate shift.Comment: Accepted at NeurIPS 202

Drug Discovery under Covariate Shift with Domain-Informed Prior Distributions over Functions

Accelerating the discovery of novel and more effective therapeutics is an important pharmaceutical problem in which deep learning is playing an increasingly significant role. However, real-world drug discovery tasks are often characterized by a scarcity of labeled data and significant covariate shift\unicode{x2013}\unicode{x2013}a setting that poses a challenge to standard deep learning methods. In this paper, we present Q-SAVI, a probabilistic model able to address these challenges by encoding explicit prior knowledge of the data-generating process into a prior distribution over functions, presenting researchers with a transparent and probabilistically principled way to encode data-driven modeling preferences. Building on a novel, gold-standard bioactivity dataset that facilitates a meaningful comparison of models in an extrapolative regime, we explore different approaches to induce data shift and construct a challenging evaluation setup. We then demonstrate that using Q-SAVI to integrate contextualized prior knowledge of drug-like chemical space into the modeling process affords substantial gains in predictive accuracy and calibration, outperforming a broad range of state-of-the-art self-supervised pre-training and domain adaptation techniques.Comment: Published in the Proceedings of the 40th International Conference on Machine Learning (ICML 2023

An Information-theoretical Approach to Semi-supervised Learning under Covariate-shift

A common assumption in semi-supervised learning is that the labeled, unlabeled, and test data are drawn from the same distribution. However, this assumption is not satisfied in many applications. In many scenarios, the data is collected sequentially (e.g., healthcare) and the distribution of the data may change over time often exhibiting so-called covariate shifts. In this paper, we propose an approach for semi-supervised learning algorithms that is capable of addressing this issue. Our framework also recovers some popular methods, including entropy minimization and pseudo-labeling. We provide new information-theoretical based generalization error upper bounds inspired by our novel framework. Our bounds are applicable to both general semi-supervised learning and the covariate-shift scenario. Finally, we show numerically that our method outperforms previous approaches proposed for semi-supervised learning under the covariate shift.Comment: Accepted at AISTATS 202

Semantic Self-adaptation: Enhancing Generalization with a Single Sample

The lack of out-of-domain generalization is a critical weakness of deep networks for semantic segmentation. Previous studies relied on the assumption of a static model, i. e., once the training process is complete, model parameters remain fixed at test time. In this work, we challenge this premise with a self-adaptive approach for semantic segmentation that adjusts the inference process to each input sample. Self-adaptation operates on two levels. First, it fine-tunes the parameters of convolutional layers to the input image using consistency regularization. Second, in Batch Normalization layers, self-adaptation interpolates between the training and the reference distribution derived from a single test sample. Despite both techniques being well known in the literature, their combination sets new state-of-the-art accuracy on synthetic-to-real generalization benchmarks. Our empirical study suggests that self-adaptation may complement the established practice of model regularization at training time for improving deep network generalization to out-of-domain data. Our code and pre-trained models are available at https://github.com/visinf/self-adaptive.Comment: Published in TMLR (July 2023); OpenReview: https://openreview.net/forum?id=ILNqQhGbLx; Code: https://github.com/visinf/self-adaptive; Video: https://youtu.be/s4DG65ic0E

Stratified Learning: a general-purpose statistical method for improved learning under Covariate Shift

Covariate shift arises when the labelled training (source) data is not representative of the unlabelled (target) data due to systematic differences in the covariate distributions. A supervised model trained on the source data subject to covariate shift may suffer from poor generalization on the target data. We propose a novel, statistically principled and theoretically justified method to improve learning under covariate shift conditions, based on propensity score stratification, a well-established methodology in causal inference. We show that the effects of covariate shift can be reduced or altogether eliminated by conditioning on propensity scores. In practice, this is achieved by fitting learners on subgroups ("strata") constructed by partitioning the data based on the estimated propensity scores, leading to balanced covariates and much-improved target prediction. We demonstrate the effectiveness of our general-purpose method on contemporary research questions in observational cosmology, and on additional benchmark examples, matching or outperforming state-of-the-art importance weighting methods, widely studied in the covariate shift literature. We obtain the best reported AUC (0.958) on the updated "Supernovae photometric classification challenge" and improve upon existing conditional density estimation of galaxy redshift from Sloan Data Sky Survey (SDSS) data

Conformal Prediction: a Unified Review of Theory and New Challenges

In this work we provide a review of basic ideas and novel developments about Conformal Prediction -- an innovative distribution-free, non-parametric forecasting method, based on minimal assumptions -- that is able to yield in a very straightforward way predictions sets that are valid in a statistical sense also in in the finite sample case. The in-depth discussion provided in the paper covers the theoretical underpinnings of Conformal Prediction, and then proceeds to list the more advanced developments and adaptations of the original idea.Comment: arXiv admin note: text overlap with arXiv:0706.3188, arXiv:1604.04173, arXiv:1709.06233, arXiv:1203.5422 by other author