Combination treatment optimization using a pan-cancer pathway model.

The design of efficient combination therapies is a difficult key challenge in the treatment of complex diseases such as cancers. The large heterogeneity of cancers and the large number of available drugs renders exhaustive in vivo or even in vitro investigation of possible treatments impractical. In recent years, sophisticated mechanistic, ordinary differential equation-based pathways models that can predict treatment responses at a molecular level have been developed. However, surprisingly little effort has been put into leveraging these models to find novel therapies. In this paper we use for the first time, to our knowledge, a large-scale state-of-the-art pan-cancer signaling pathway model to identify candidates for novel combination therapies to treat individual cancer cell lines from various tissues (e.g., minimizing proliferation while keeping dosage low to avoid adverse side effects) and populations of heterogeneous cancer cell lines (e.g., minimizing the maximum or average proliferation across the cell lines while keeping dosage low). We also show how our method can be used to optimize the drug combinations used in sequential treatment plans-that is, optimized sequences of potentially different drug combinations-providing additional benefits. In order to solve the treatment optimization problems, we combine the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm with a significantly more scalable sampling scheme for truncated Gaussian distributions, based on a Hamiltonian Monte-Carlo method. These optimization techniques are independent of the signaling pathway model, and can thus be adapted to find treatment candidates for other complex diseases than cancers as well, as long as a suitable predictive model is available.

Using machine learning to improve survival prediction after heart transplantation.

BACKGROUND: This study investigates the use of modern machine learning (ML) techniques to improve prediction of survival after orthotopic heart transplantation (OHT). METHODS: Retrospective study of adult patients undergoing primary, isolated OHT between 2000 and 2019 as identified in the United Network for Organ Sharing (UNOS) registry. The primary outcome was 1-year post-transplant survival. Patients were randomly divided into training (80%) and validation (20%) sets. Dimensionality reduction and data re-sampling were employed during training. Multiple machine learning algorithms were combined into a final ensemble ML model. The discriminatory capability was assessed using the area under receiver-operating-characteristic curve (AUROC), net reclassification index (NRI), and decision curve analysis (DCA). RESULTS: A total of 33,657 OHT patients were evaluated. One-year mortality was 11% (n = 3738). In the validation cohort, the AUROC of singular logistic regression was 0.649 (95% CI, 0.628-0.670) compared to 0.691 (95% CI, 0.671-0.711) with random forest, 0.691 (95% CI, 0.671-0.712) with deep neural network, and 0.653 (95% CI, 0.632-0.674) with Adaboost. A final ensemble ML model was created that demonstrated the greatest improvement in AUROC: 0.764 (95% CI, 0.745-0.782) (p < .001). The ensemble ML model improved predictive performance by 72.9% ±3.8% (p < .001) as assessed by NRI compared to logistic regression. DCA showed the final ensemble method improved risk prediction across the entire spectrum of predicted risk as compared to all other models (p < .001). CONCLUSIONS: Modern ML techniques can improve risk prediction in OHT compared to traditional approaches. This may have important implications in patient selection, programmatic evaluation, allocation policy, and patient counseling and prognostication.

A nonsimultaneous, extended, altruistic-donor chain.

We report a chain of 10 kidney transplantations, initiated in July 2007 by a single altruistic donor (i.e., a donor without a designated recipient) and coordinated over a period of 8 months by two large paired-donation registries. These transplantations involved six transplantation centers in five states. In the case of five of the transplantations, the donors and their coregistered recipients underwent surgery simultaneously. In the other five cases, "bridge donors" continued the chain as many as 5 months after the coregistered recipients in their own pairs had received transplants. This report of a chain of paired kidney donations, in which the transplantations were not necessarily performed simultaneously, illustrates the potential of this strategy.

Superhuman AI for multiplayer poker.

In recent years there have been great strides in artificial intelligence (AI), with games often serving as challenge problems, benchmarks, and milestones for progress. Poker has served for decades as such a challenge problem. Past successes in such benchmarks, including poker, have been limited to two-player games. However, poker in particular is traditionally played with more than two players. Multiplayer games present fundamental additional issues beyond those in two-player games, and multiplayer poker is a recognized AI milestone. In this paper we present Pluribus, an AI that we show is stronger than top human professionals in six-player no-limit Texas hold'em poker, the most popular form of poker played by humans.

Superhuman AI for heads-up no-limit poker: Libratus beats top professionals.

No-limit Texas hold'em is the most popular form of poker. Despite artificial intelligence (AI) successes in perfect-information games, the private information and massive game tree have made no-limit poker difficult to tackle. We present Libratus, an AI that, in a 120,000-hand competition, defeated four top human specialist professionals in heads-up no-limit Texas hold'em, the leading benchmark and long-standing challenge problem in imperfect-information game solving. Our game-theoretic approach features application-independent techniques: an algorithm for computing a blueprint for the overall strategy, an algorithm that fleshes out the details of the strategy for subgames that are reached during play, and a self-improver algorithm that fixes potential weaknesses that opponents have identified in the blueprint strategy.