A patient's digital twin is a computational model that describes the evolution of their health over time. Digital twins have the potential to revolutionize medicine by enabling individual-level computer simulations of human health, which can be used to conduct more efficient clinical trials or to recommend personalized treatment options. Due to the overwhelming complexity of human biology, machine learning approaches that leverage large datasets of historical patients' longitudinal health records to generate patients' digital twins are more tractable than potential mechanistic models. In this manuscript, we describe a neural network architecture that can learn conditional generative models of clinical trajectories, which we call Digital Twin Generators (DTGs), that can create digital twins of individual patients. We show that the same neural network architecture can be trained to generate accurate digital twins for patients across 13 different indications simply by changing the training set and tuning hyperparameters. By introducing a general purpose architecture, we aim to unlock the ability to scale machine learning approaches to larger datasets and across more indications so that a digital twin could be created for any patient in the world.

Randomized controlled trials (RCTs) with binary primary endpoints introduce novel challenges for inferring the causal effects of treatments. The most significant challenge is non-collapsibility, in which the conditional odds ratio estimand under covariate adjustment differs from the unconditional estimand in the logistic regression analysis of RCT data. This issue gives rise to apparent paradoxes, such as the variance of the estimator for the conditional odds ratio from a covariate-adjusted model being greater than the variance of the estimator from the unadjusted model. We address this challenge in the context of adjustment based on predictions of control outcomes from generative artificial intelligence (AI) algorithms, which are referred to as prognostic scores. We demonstrate that prognostic score adjustment in logistic regression increases the power of the Wald test for the conditional odds ratio under a fixed sample size, or alternatively reduces the necessary sample size to achieve a desired power, compared to the unadjusted analysis. We derive formulae for prospective calculations of the power gain and sample size reduction that can result from adjustment for the prognostic score. Furthermore, we utilize g-computation to expand the scope of prognostic score adjustment to inferences on the marginal risk difference, relative risk, and odds ratio estimands. We demonstrate the validity of our formulae via extensive simulation studies that encompass different types of logistic regression model specifications. Our simulation studies also indicate how prognostic score adjustment can reduce the variance of g-computation estimators for the marginal estimands while maintaining frequentist properties such as asymptotic unbiasedness and Type I error rate control. Our methodology can ultimately enable more definitive and conclusive analyses for RCTs with binary primary endpoints.

Effective and rapid decision-making from randomized controlled trials (RCTs) requires unbiased and precise treatment effect inferences. Two strategies to address this requirement are to adjust for covariates that are highly correlated with the outcome, and to leverage historical control information via Bayes' theorem. We propose a new Bayesian prognostic covariate adjustment methodology, referred to as Bayesian PROCOVA, that combines these two strategies. Covariate adjustment in Bayesian PROCOVA is based on generative artificial intelligence (AI) algorithms that construct a digital twin generator (DTG) for RCT participants. The DTG is trained on historical control data and yields a digital twin (DT) probability distribution for each RCT participant's outcome under the control treatment. The expectation of the DT distribution, referred to as the prognostic score, defines the covariate for adjustment. Historical control information is leveraged via an additive mixture prior with two components: an informative prior probability distribution specified based on historical control data, and a weakly informative prior distribution. The mixture weight determines the extent to which posterior inferences are drawn from the informative component, versus the weakly informative component. This weight has a prior distribution as well, and so the entire additive mixture prior is completely pre-specifiable without involving any RCT information. We establish an efficient Gibbs algorithm for sampling from the posterior distribution, and derive closed-form expressions for the posterior mean and variance of the treatment effect parameter conditional on the weight, in Bayesian PROCOVA. We evaluate efficiency gains of Bayesian PROCOVA via its bias control and variance reduction compared to frequentist PROCOVA in simulation studies that encompass different discrepancies. These gains translate to smaller RCTs.

A crucial task for a randomized controlled trial (RCT) is to specify a statistical method that can yield an efficient estimator and powerful test for the treatment effect. A novel and effective strategy to obtain efficient and powerful treatment effect inferences is to incorporate predictions from generative artificial intelligence (AI) algorithms into covariate adjustment for the regression analysis of a RCT. Training a generative AI algorithm on historical control data enables one to construct a digital twin generator (DTG) for RCT participants, which utilizes a participant's baseline covariates to generate a probability distribution for their potential control outcome. Summaries of the probability distribution from the DTG are highly predictive of the trial outcome, and adjusting for these features via regression can thus improve the quality of treatment effect inferences, while satisfying regulatory guidelines on statistical analyses, for a RCT. However, a critical assumption in this strategy is homoskedasticity, or constant variance of the outcome conditional on the covariates. In the case of heteroskedasticity, existing covariate adjustment methods yield inefficient estimators and underpowered tests. We propose to address heteroskedasticity via a weighted prognostic covariate adjustment methodology (Weighted PROCOVA) that adjusts for both the mean and variance of the regression model using information obtained from the DTG. We prove that our method yields unbiased treatment effect estimators, and demonstrate via comprehensive simulation studies and case studies from Alzheimer's disease that it can reduce the variance of the treatment effect estimator, maintain the Type I error rate, and increase the power of the test for the treatment effect from 80% to 85%~90% when the variances from the DTG can explain 5%~10% of the variation in the RCT participants' outcomes.

Conditional generative models are capable of using contextual information as input to create new imaginative outputs. Conditional Restricted Boltzmann Machines (CRBMs) are one class of conditional generative models that have proven to be especially adept at modeling noisy discrete or continuous data, but the lack of expressivity in CRBMs have limited their widespread adoption. Here we introduce Neural Boltzmann Machines (NBMs) which generalize CRBMs by converting each of the CRBM parameters to their own neural networks that are allowed to be functions of the conditional inputs. NBMs are highly flexible conditional generative models that can be trained via stochastic gradient descent to approximately maximize the log-likelihood of the data. We demonstrate the utility of NBMs especially with normally distributed data which has historically caused problems for Gaussian-Bernoulli CRBMs.

Unlearn.AI, Inc., 75 Hawthorne St. Ste 560, San Francisco, CA 94105 (Dated: November 7, 2022) Restricted Boltzmann Machines (RBMs) are probabilistic generative models that can be trained by maximum likelihood in principle, but are usually trained by an approximate algorithm called Contrastive Divergence (CD) in practice. In general, a CD-k algorithm estimates an average with respect to the model distribution using a sample obtained from a k-step Markov Chain Monte Carlo Algorithm (e.g., block Gibbs sampling) starting from some initial configuration. Choices of k typically vary from 1 to 100. This technical report explores if it's possible to leverage a simple approximate sampling algorithm with a modified version of CD in order to train an RBM with k=0. As usual, the method is illustrated on MNIST.

A patient is more than one number, yet most approaches to machine learning from electronic health data can only predict a single endpoint. Here, we present an alternative -- using unsupervised deep learning to simulate detailed patient trajectories. We use data comprising 18-month longitudinal trajectories of 42 clinical variables from 1908 patients with Mild Cognitive Impairment (MCI) or Alzheimer's Disease (AD) to train a model for personalized forecasting of disease progression. Our model simulates the evolution of each sub-component of cognitive exams, laboratory tests, and their associations with baseline clinical characteristics, generating both predictions and their confidence intervals. Even though it is not trained to predict changes in disease severity, our unsupervised model predicts changes in total ADAS-Cog scores with the same accuracy as specifically trained supervised models. We show how simulations can be used to interpret our model and demonstrate how to create synthetic control arm data for AD clinical trials. Our model's ability to simultaneously predict dozens of characteristics of a patient at any point in the future is a crucial step forward in computational precision medicine.

Restricted Boltzmann Machines (RBMs) are a class of generative neural network that are typically trained to maximize a log-likelihood objective function. We argue that likelihood-based training strategies may fail because the objective does not sufficiently penalize models that place a high probability in regions where the training data distribution has low probability. To overcome this problem, we introduce Boltzmann Encoded Adversarial Machines (BEAMs). A BEAM is an RBM trained against an adversary that uses the hidden layer activations of the RBM to discriminate between the training data and the probability distribution generated by the model. We present experiments demonstrating that BEAMs outperform RBMs and GANs on multiple benchmarks.

Machine Learning (ML) is one of the most exciting and dynamic areas of modern research and application. The purpose of this review is to provide an introduction to the core concepts and tools of machine learning in a manner easily understood and intuitive to physicists. The review begins by covering fundamental concepts in ML and modern statistics such as the bias-variance tradeoff, overfitting, regularization, and generalization before moving on to more advanced topics in both supervised and unsupervised learning. Topics covered in the review include ensemble models, deep learning and neural networks, clustering and data visualization, energy-based models (including MaxEnt models and Restricted Boltzmann Machines), and variational methods. Throughout, we emphasize the many natural connections between ML and statistical physics. A notable aspect of the review is the use of Python notebooks to introduce modern ML/statistical packages to readers using physics-inspired datasets (the Ising Model and Monte-Carlo simulations of supersymmetric decays of proton-proton collisions). We conclude with an extended outlook discussing possible uses of machine learning for furthering our understanding of the physical world as well as open problems in ML where physicists maybe able to contribute. (Notebooks are available at https://physics.bu.edu/~pankajm/MLnotebooks.html )

Identifying small subsets of features that are relevant for prediction and/or classification tasks is a central problem in machine learning and statistics. The feature selection task is especially important, and computationally difficult, for modern datasets where the number of features can be comparable to, or even exceed, the number of samples. Here, we show that feature selection with Bayesian inference takes a universal form and reduces to calculating the magnetizations of an Ising model, under some mild conditions. Our results exploit the observation that the evidence takes a universal form for strongly-regularizing priors --- priors that have a large effect on the posterior probability even in the infinite data limit. We derive explicit expressions for feature selection for generalized linear models, a large class of statistical techniques that include linear and logistic regression. We illustrate the power of our approach by analyzing feature selection in a logistic regression-based classifier trained to distinguish between the letters B and D in the notMNIST dataset.