Response heterogeneity: Challenges for personalised medicine and big data approaches in psychiatry and chronic pain

Response rates to available treatments for psychological and chronic pain disorders are poor, and there is a considerable burden of suffering and disability for patients, who often cycle through several rounds of ineffective treatment. As individuals presenting to the clinic with symptoms of these disorders are likely to be heterogeneous, there is considerable interest in the possibility that different constellations of signs could be used to identify subgroups of patients that might preferentially benefit from particular kinds of treatment. To this end, there has been a recent focus on the application of machine learning methods to attempt to identify sets of predictor variables (demographic, genetic, etc.) that could be used to target individuals towards treatments that are more likely to work for them in the first instance. Importantly, the training of such models generally relies on datasets where groups of individual predictor variables are labelled with a binary outcome category − usually ‘responder’ or ‘non-responder’ (to a particular treatment). However, as previously highlighted in other areas of medicine, there is a basic statistical problem in classifying individuals as ‘responding’ to a particular treatment on the basis of data from conventional randomized controlled trials. Specifically, insufficient information on the partition of variance components in individual symptom changes mean that it is inappropriate to consider data from the active treatment arm alone in this way. This may be particularly problematic in the case of psychiatric and chronic pain symptom data, where both within-subject variability and measurement error are likely to be high. Here, we outline some possible solutions to this problem in terms of dataset design and machine learning methodology, and conclude that it is important to carefully consider the kind of inferences that particular training data are able to afford, especially in arenas where the potential clinical benefit is so large

Simulation Intelligence: Towards a New Generation of Scientific Methods

The original "Seven Motifs" set forth a roadmap of essential methods for the field of scientific computing, where a motif is an algorithmic method that captures a pattern of computation and data movement. We present the "Nine Motifs of Simulation Intelligence", a roadmap for the development and integration of the essential algorithms necessary for a merger of scientific computing, scientific simulation, and artificial intelligence. We call this merger simulation intelligence (SI), for short. We argue the motifs of simulation intelligence are interconnected and interdependent, much like the components within the layers of an operating system. Using this metaphor, we explore the nature of each layer of the simulation intelligence operating system stack (SI-stack) and the motifs therein: (1) Multi-physics and multi-scale modeling; (2) Surrogate modeling and emulation; (3) Simulation-based inference; (4) Causal modeling and inference; (5) Agent-based modeling; (6) Probabilistic programming; (7) Differentiable programming; (8) Open-ended optimization; (9) Machine programming. We believe coordinated efforts between motifs offers immense opportunity to accelerate scientific discovery, from solving inverse problems in synthetic biology and climate science, to directing nuclear energy experiments and predicting emergent behavior in socioeconomic settings. We elaborate on each layer of the SI-stack, detailing the state-of-art methods, presenting examples to highlight challenges and opportunities, and advocating for specific ways to advance the motifs and the synergies from their combinations. Advancing and integrating these technologies can enable a robust and efficient hypothesis-simulation-analysis type of scientific method, which we introduce with several use-cases for human-machine teaming and automated science