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.

Cyclical MCMC is a novel MCMC framework recently proposed by Zhang et al. (2019) to address the challenge posed by high-dimensional multimodal posterior distributions like those arising in deep learning. The algorithm works by generating a nonhomogeneous Markov chain that tracks - cyclically in time - tempered versions of the target distribution. We show in this work that cyclical MCMC converges to the desired probability distribution in settings where the Markov kernels used are fast mixing, and sufficiently long cycles are employed. However in the far more common settings of slow mixing kernels, the algorithm may fail to produce samples from the desired distribution. In particular, in a simple mixture example with unequal variance where powering is known to produce slow mixing kernels, we show by simulation that cyclical MCMC fails to converge to the desired limit. Finally, we show that cyclical MCMC typically estimates well the local shape of the target distribution around each mode, even when we do not have convergence to the target.

Informed importance tempering (IIT) is an easy-to-implement MCMC algorithm that can be seen as an extension of the familiar Metropolis-Hastings algorithm with the special feature that informed proposals are always accepted, and which was shown in Zhou and Smith (2022) to converge much more quickly in some common circumstances. This work develops a new, comprehensive guide to the use of IIT in many situations. First, we propose two IIT schemes that run faster than existing informed MCMC methods on discrete spaces by not requiring the posterior evaluation of all neighboring states. Second, we integrate IIT with other MCMC techniques, including simulated tempering, pseudo-marginal and multiple-try methods (on general state spaces), which have been conventionally implemented as Metropolis-Hastings schemes and can suffer from low acceptance rates. The use of IIT allows us to always accept proposals and brings about new opportunities for optimizing the sampler which are not possible under the Metropolis-Hastings framework. Numerical examples illustrating our findings are provided for each proposed algorithm, and a general theory on the complexity of IIT methods is developed.

Hamiltonian Monte Carlo (HMC) is a very popular and generic collection of Markov chain Monte Carlo (MCMC) algorithms. One explanation for the popularity of HMC algorithms is their excellent performance as the dimension $d$ of the target becomes large: under conditions that are satisfied for many common statistical models, optimally-tuned HMC algorithms have a running time that scales like $d^{0.25}$. In stark contrast, the running time of the usual Random-Walk Metropolis (RWM) algorithm, optimally tuned, scales like $d$. This superior scaling of the HMC algorithm with dimension is attributed to the fact that it, unlike RWM, incorporates the gradient information in the proposal distribution. In this paper, we investigate a different scaling question: does HMC beat RWM for highly $\textit{multimodal}$ targets? We find that the answer is often $\textit{no}$. We compute the spectral gaps for both the algorithms for a specific class of multimodal target densities, and show that they are identical. The key reason is that, within one mode, the gradient is effectively ignorant about other modes, thus negating the advantage the HMC algorithm enjoys in unimodal targets. We also give heuristic arguments suggesting that the above observation may hold quite generally. Our main tool for answering this question is a novel simple formula for the conductance of HMC using Liouville's theorem. This result allows us to compute the spectral gap of HMC algorithms, for both the classical HMC with isotropic momentum and the recent Riemannian HMC, for multimodal targets.