Validated Synthetic Patient Generation for Small Longitudinal Cohorts: Coagulation Dynamics Across Pregnancy

TL;DR

This paper introduces a novel generative framework called multiplicity-weighted Stochastic Attention (SA) that creates realistic synthetic longitudinal patient data, facilitating modeling in small cohorts such as pregnant women.

Contribution

The paper presents a new generative method based on Hopfield network theory that produces indistinguishable synthetic patients from small longitudinal datasets, including rare subgroups.

Findings

Synthetic patients are statistically and mechanistically indistinguishable from real patients.

SA-generated data enables accurate outcome prediction comparable to real data.

Method effectively amplifies rare clinical subgroups without retraining.

Abstract

Small longitudinal clinical cohorts, common in maternal health, rare diseases, and early-phase trials, limit computational modeling: too few patients to train reliable models, yet too costly and slow to expand through additional enrollment. We present multiplicity-weighted Stochastic Attention (SA), a generative framework based on modern Hopfield network theory that addresses this gap. SA embeds real patient profiles as memory patterns in a continuous energy landscape and generates novel synthetic patients via Langevin dynamics that interpolate between stored patterns while preserving the geometry of the original cohort. Per-pattern multiplicity weights enable targeted amplification of rare clinical subgroups at inference time without retraining. We applied SA to a longitudinal coagulation dataset from 23 pregnant patients spanning 72 biochemical features across 3 visits (pre-pregnancy baseline, first trimester, and third trimester), including rare subgroups such as polycystic ovary syndrome and preeclampsia. Synthetic patients generated by SA were statistically, structurally, and mechanistically indistinguishable from their real counterparts across multiple independent validation tests, including an ordinary differential equation model of the coagulation cascade. A downstream utility test further showed that a mechanistic model calibrated entirely on synthetic patients predicted held-out real patient outcomes as well as one calibrated on real data. These results demonstrate that SA can produce clinically useful synthetic cohorts from very small longitudinal datasets, enabling data-augmented modeling in small-cohort settings.