Mathematical modelling for health systems research: a systematic review of system dynamics and agent-based models.

BACKGROUND: Mathematical modelling has been a vital research tool for exploring complex systems, most recently to aid understanding of health system functioning and optimisation. System dynamics models (SDM) and agent-based models (ABM) are two popular complementary methods, used to simulate macro- and micro-level health system behaviour. This systematic review aims to collate, compare and summarise the application of both methods in this field and to identify common healthcare settings and problems that have been modelled using SDM and ABM. METHODS: We searched MEDLINE, EMBASE, Cochrane Library, MathSciNet, ACM Digital Library, HMIC, Econlit and Global Health databases to identify literature for this review. We described papers meeting the inclusion criteria using descriptive statistics and narrative synthesis, and made comparisons between the identified SDM and ABM literature. RESULTS: We identified 28 papers using SDM methods and 11 papers using ABM methods, one of which used hybrid SDM-ABM to simulate health system behaviour. The majority of SDM, ABM and hybrid modelling papers simulated health systems based in high income countries. Emergency and acute care, and elderly care and long-term care services were the most frequently simulated health system settings, modelling the impact of health policies and interventions such as those targeting stretched and under resourced healthcare services, patient length of stay in healthcare facilities and undesirable patient outcomes. CONCLUSIONS: Future work should now turn to modelling health systems in low- and middle-income countries to aid our understanding of health system functioning in these settings and allow stakeholders and researchers to assess the impact of policies or interventions before implementation. Hybrid modelling of health systems is still relatively novel but with increasing software developments and a growing demand to account for both complex system feedback and heterogeneous behaviour exhibited by those who access or deliver healthcare, we expect a boost in their use to model health systems

Environmental and genetic predictors of human cardiovascular ageing

Abstract Cardiovascular ageing is a process that begins early in life and leads to a progressive change in structure and decline in function due to accumulated damage across diverse cell types, tissues and organs contributing to multi-morbidity. Damaging biophysical, metabolic and immunological factors exceed endogenous repair mechanisms resulting in a pro-fibrotic state, cellular senescence and end-organ damage, however the genetic architecture of cardiovascular ageing is not known. Here we use machine learning approaches to quantify cardiovascular age from image-derived traits of vascular function, cardiac motion and myocardial fibrosis, as well as conduction traits from electrocardiograms, in 39,559 participants of UK Biobank. Cardiovascular ageing is found to be significantly associated with common or rare variants in genes regulating sarcomere homeostasis, myocardial immunomodulation, and tissue responses to biophysical stress. Ageing is accelerated by cardiometabolic risk factors and we also identify prescribed medications that are potential modifiers of ageing. Through large-scale modelling of ageing across multiple traits our results reveal insights into the mechanisms driving premature cardiovascular ageing and reveal potential molecular targets to attenuate age-related processes

Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; P&lt;0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; P=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M1: 0.86-0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.</p