Toward precision medicine using a “digital twin” approach: modeling the onset of disease-specific brain atrophy in individuals with multiple sclerosis

Abstract

Digital Twin (DT) is a novel concept that may bring a paradigm shift for precision medicine. In this study we demonstrate a DT application for estimating the age of onset of disease-specific brain atrophy in individuals with multiple sclerosis (MS) using brain MRI. We first augmented longitudinal data from a well-fitted spline model derived from a large cross-sectional normal aging data. Then we compared different mixed spline models through both simulated and real-life data and identified the mixed spline model with the best fit. Using the appropriate covariate structure selected from 52 different candidate structures, we augmented the thalamic atrophy trajectory over the lifespan for each individual MS patient and a corresponding hypothetical twin with normal aging. Theoretically, the age at which the brain atrophy trajectory of an MS patient deviates from the trajectory of their hypothetical healthy twin can be considered as the onset of progressive brain tissue loss. With a tenfold cross validation procedure through 1000 bootstrapping samples, we found the onset age of progressive brain tissue loss was, on average, 5–6 years prior to clinical symptom onset. Our novel approach also discovered two clear patterns of patient clusters: earlier onset versus simultaneous onset of brain atrophy.

The effectiveness of digital twins in promoting precision health across the entire population: a systematic review

“…The primary challenges in these quasi-experimental studies were due to the lack of control groups, inadequate baseline comparisons, and limited follow-up reporting. Four out of five (80.00%) 17 , 20 , 22 , 23 of the cohort studies met or exceeded the criterion with at least eight positive responses, demonstrating their acceptable quality. However, one study (20.00%) 24 had a lower score due to incomplete data regarding loss to follow-up and the specifics of the interventions applied.…”

“…The studies included in this systematic review were published between 2021 (2/12, 16.67%) 23 , 24 and 2023 (8/12, 66.67%) 13 – 20 . Originating from diverse regions, 4/12 studies (33.33%) were from Asia 13 , 14 , 21 , 24 , 5/12 (41.67%) from America 15 , 17 , 19 , 20 , 22 , and 3/12 (25.00%) from Europe 16 , 18 , 23 . The review encompassed various study designs, including randomized controlled trials (1/12, 8.33%) 14 , quasi-experiments (6/12, 50.00%) 13 , 15 , 16 , 18 , 19 , 21 , and cohort studies (5/12, 41.67%) 17 , 20 , 22 – 24 .…”

“…The sample sizes ranged from 15 13 to 3500 patients 19 . Five studies assessed the impact of digital twins on virtual patients 15 , 16 , 18 – 20 , while seven examined their effect on real-world patients 13 , 14 , 17 , 21 – 24 . These patients included had various diseases, including cancer (4/12, 33.33%) 15 , 16 , 19 , 22 , type 2 diabetes (2/12, 16.66%) 13 , 14 , multiple sclerosis (2/12, 16.66%) 17 , 18 , qi deficiency (1/12, 8.33%) 21 , heart failure (1/12, 8.33%) 20 , post-hepatectomy liver failure (1/12, 8.33%) 23 , and dental issues (1/12, 8.33%) 24 .…”

“…Five studies assessed the impact of digital twins on virtual patients 15 , 16 , 18 – 20 , while seven examined their effect on real-world patients 13 , 14 , 17 , 21 – 24 . These patients included had various diseases, including cancer (4/12, 33.33%) 15 , 16 , 19 , 22 , type 2 diabetes (2/12, 16.66%) 13 , 14 , multiple sclerosis (2/12, 16.66%) 17 , 18 , qi deficiency (1/12, 8.33%) 21 , heart failure (1/12, 8.33%) 20 , post-hepatectomy liver failure (1/12, 8.33%) 23 , and dental issues (1/12, 8.33%) 24 . This review coded interventions into three types: personalized health management (3/12, 25.00%) 13 , 14 , 21 , precision individual therapy effects (3/12, 25.00%) 15 , 16 , 18 – 20 , 22 , and predicting individual risk (3/12, 25.00%) 17 , 23 , 24 , with a total of 45 measured outcomes.…”

Instability of excitatory synapses in experimental autoimmune encephalomyelitis and the outcome for excitatory circuit inputs to individual cortical neurons

“…How synapse loss and dysfunction in MS contribute to physical neurologic disability and the cognitive dysfunction that impacts the majority of PwMS (Benedict et al, 2020) is unknown, but it may be an essential contributor (Filippo et al, 2018). Most post-mortem studies of synapse loss in people who had MS are from patients with longstanding disease (Möck et al, 2021), but it is likely that this synapse loss begins early in the disease (Bevan et al, 2018), possibly even before the onset of the first relapse symptoms (Azevedo et al, 2015;Bjornevik et al, 2020;Cen et al, 2023;Cortese et al, 2016), and is accelerated by inflammatory disease activity (Cagol et al, 2022). While the mechanisms of synapse loss remain poorly understood, it is not simply the result of demyelination and axonal transection (Jürgens et al, 2016); rather, inflammation shapes synapses even far from demyelinating lesions.…”