Timelines of events, such as symptom appearance or a change in biomarker value, provide powerful signatures that characterise progressive diseases. Understanding and predicting the timing of events is important for clinical trials targeting individuals early in the disease course when putative treatments are likely to have the strongest effect. However, previous models of disease progression cannot estimate the time between events and provide only an ordering in which they change. Here, we introduce the temporal event-based model (TEBM), a new probabilistic model for inferring timelines of biomarker events from sparse and irregularly sampled datasets. We demonstrate the power of the TEBM in two neurodegenerative conditions: Alzheimer\'s disease (AD) and Huntington\'s disease (HD). In both diseases, the TEBM not only recapitulates current understanding of event orderings but also provides unique new ranges of timescales between consecutive events. We reproduce and validate these findings using external datasets in both diseases. We also demonstrate that the TEBM improves over current models; provides unique stratification capabilities; and enriches simulated clinical trials to achieve a power of 80% with less than half the cohort size compared with random selection. The application of the TEBM naturally extends to a wide range of progressive conditions.

Alzheimer\'s disease and related dementia (ADRD) are characterized by multiple and progressive anatomo-clinical changes including accumulation of abnormal proteins in the brain, brain atrophy and severe cognitive impairment. Understanding the sequence and timing of these changes is of primary importance to gain insight into the disease natural history and ultimately allow earlier diagnosis. Yet, modeling changes over disease course from cohort data is challenging as the usual timescales (time since inclusion, chronological age) are inappropriate and time-to-clinical diagnosis is available on small subsamples of participants with short follow-up durations prior to diagnosis. One solution to circumvent this challenge is to define the disease time as a latent variable.
We developed a multivariate mixed model approach that realigns individual trajectories into the latent disease time to describe disease progression. In contrast with the existing literature, our methodology exploits the clinical diagnosis information as a partially observed and approximate reference to guide the estimation of the latent disease time. The model estimation was carried out in the Bayesian Framework using Stan. We applied the methodology to the MEMENTO study, a French multicentric clinic-based cohort of 2186 participants with 5-year intensive follow-up. Repeated measures of 12 ADRD markers stemmed from cerebrospinal fluid (CSF), brain imaging and cognitive tests were analyzed.
The estimated latent disease time spanned over twenty years before the clinical diagnosis. Considering the profile of a woman aged 70 with a high level of education and APOE4 carrier (the main genetic risk factor for ADRD), CSF markers of tau proteins accumulation preceded markers of brain atrophy by 5 years and cognitive decline by 10 years. However we observed that individual characteristics could substantially modify the sequence and timing of these changes, in particular for CSF level of A[Formula: see text].
By leveraging the available clinical diagnosis timing information, our disease progression model does not only realign trajectories into the most homogeneous way. It accounts for the inherent residual inter-individual variability in dementia progression to describe the long-term anatomo-clinical degradations according to the years preceding clinical diagnosis, and to provide clinically meaningful information on the sequence of events.
clinicaltrials.gov, NCT01926249. Registered on 16 August 2013.

Alzheimer\'s disease (AD) is a complex form of dementia and due to its high phenotypic variability, its diagnosis and monitoring can be quite challenging. Biomarkers play a crucial role in AD diagnosis and monitoring, but interpreting these biomarkers can be problematic due to their spatial and temporal heterogeneity. Therefore, researchers are increasingly turning to imaging-based biomarkers that employ data-driven computational approaches to examine the heterogeneity of AD. In this comprehensive review article, we aim to provide health professionals with a comprehensive view of past applications of data-driven computational approaches in studying AD heterogeneity and planning future research directions. We first define and offer basic insights into different categories of heterogeneity analysis, including spatial heterogeneity, temporal heterogeneity, and spatial-temporal heterogeneity. Then, we scrutinize 22 articles relating to spatial heterogeneity, 14 articles relating to temporal heterogeneity, and five articles relating to spatial-temporal heterogeneity, highlighting the strengths and limitations of these strategies. Furthermore, we discuss the importance of understanding spatial heterogeneity in AD subtypes and their clinical manifestations, biomarkers for abnormal orderings and AD stages, the recent advancements in spatial-temporal heterogeneity analysis for AD, and the emerging role of omics data integration in advancing personalized diagnosis and treatment for AD patients. By emphasizing the significance of understanding AD heterogeneity, we hope to stimulate further research in this field to facilitate the development of personalized interventions for AD patients.

This paper proposes a disease progression model for early stage Parkinson\'s Disease (PD) based on DaTscan images. The model has two novel aspects: first, the model is fully coupled across the two caudates and putamina. Second, the model uses a new constraint called model mirror symmetry (MMS). A full Bayesian analysis, with collapsed Gibbs sampling using conjugate priors, is used to obtain posterior samples of the model parameters. The model identifies PD progression subtypes and reveals novel fast modes of PD progression.

The prediction of Alzheimer\'s disease (AD) progression plays a very important role in the early intervention of patients and the improvement of life quality. Cognitive scales are commonly used to assess the patient\'s status. However, due to the complicated pathogenesis of AD and the individual differences in AD, the prediction of AD progression is challenging. This paper proposes a novel coupling model (P-E model) that takes into account the processes of physiological degradation and emotional state transition of AD patients. We conduct experiments on synthetic data to validate the effectiveness of the proposed P-E model. Next, we conduct experiments on 134 subjects with more than 10 follow-ups from the Alzheimer\'s Disease Neuroimaging Initiative. The prediction performance of the P-E model is significantly better than other state-of-the-art methods, which achieves the mean squared error of 7.137 ± 0.035. The experimental results show that the P-E model can well characterize the non-monotonic properties of AD cognitive data and can also have a good predictive ability for time series data with individual differences.

Mixed models for repeated measures (MMRMs) are ubiquitous when analyzing outcomes of clinical trials. However, the linearity of the fixed-effect structure in these models largely restrict their use to estimating treatment effects that are defined as linear combinations of effects on the outcome scale. In some situations, alternative quantifications of treatment effects may be more appropriate. In progressive diseases, for example, one may want to estimate if a drug has cumulative effects resulting in increasing efficacy over time or whether it slows the time progression of disease. This article introduces a class of nonlinear mixed-effects models called progression models for repeated measures (PMRMs) that, based on a continuous-time extension of the categorical-time parametrization of MMRMs, enables estimation of novel types of treatment effects, including measures of slowing or delay of the time progression of disease. Compared to conventional estimates of treatment effects where the unit matches that of the outcome scale (eg, 2 points benefit on a cognitive scale), the time-based treatment effects can offer better interpretability and clinical meaningfulness (eg, 6 months delay in progression of cognitive decline). The PMRM class includes conventionally used MMRMs and related models for longitudinal data analysis, as well as variants of previously proposed disease progression models as special cases. The potential of the PMRM framework is illustrated using both simulated and historical data from clinical trials in Alzheimer\'s disease with different types of artificially simulated treatment effects. Compared to conventional models it is shown that PMRMs can offer substantially increased power to detect disease-modifying treatment effects where the benefit is increasing with treatment duration.

People live a long time in pre-diabetes/early diabetes without a formal diagnosis or management. Heterogeneity of progression coupled with deficiencies in electronic health records related to incomplete data, discrete events, and irregular event intervals make identification of pre-diabetes and critical points of diabetes progression challenging.
We utilized longitudinal electronic health records of 9298 patients with type 2 diabetes or prediabetes from 2005 to 2016 from a large regional healthcare delivery network in China. We optimized a generative Markov-Bayesian-based model to generate 5000 synthetic illness trajectories. The synthetic data were manually reviewed by endocrinologists.
We build an optimized generative progression model for type 2 diabetes using anchor information to reduce the number of parameters learning in the third layer of the model from [Formula: see text] to [Formula: see text], where [Formula: see text] is the number of clinical findings, [Formula: see text] is the number of complications, [Formula: see text] is the number of anchors. Based on this model, we infer the relationships between progression stages, the onset of complication categories, and the associated diagnoses during the whole progression of type 2 diabetes using electronic health records.
Our findings indicate that 55.3% of single complications and 31.8% of complication patterns could be predicted early and managed appropriately to potentially delay (as it is a progressive disease) or prevented (by lifestyle modifications that keep patient from developing/triggering diabetes in the first place).
The full type 2 diabetes patient trajectories generated by the chronic disease progression model can counter a lack of real-world evidence of desired longitudinal timeframe while facilitating population health management.

Mucopolysaccaridosis IIIA (MPS IIIA) is a rare genetic disease that afflicts children and leads to neurocognitive degeneration. We develop a Bayesian disease progression model (DPM) of MPS IIIA that characterizes the pattern of cognitive growth and decline in this disease. The DPM is a repeated measures model that incorporates a nonlinear developmental trajectory and shape-invariant random effects. This approach quantifies the pattern of cognitive development in MPS IIIA and addresses differences in biological age, length of follow-up, and clinical outcomes across natural history subjects. The DPM can be used in clinical trials to estimate the percent slowing in disease progression for treatment relative to natural history. Simulations demonstrate that the DPM provides substantial improvements in power relative to alternative analyses.

The use of Disease progression models (DPMs) in Drug Development has been widely adopted across therapeutic areas as a method for integrating previously obtained disease knowledge to elucidate the impact of novel therapeutics or vaccines on disease course, thus quantifying the potential clinical benefit at different stages of drug development programs. This paper provides a brief overview of DPMs and the evolution in data types, analytic methods, and applications that have occurred in their use by Quantitive Clinical Pharmacologists. It also provides examples of how these models have informed decisions and clinical trial design across several therapeutic areas and at various stages of development. It briefly describes potential new applications of DPMs utilizing emerging data sources, and utilizing new analytic techniques, and discuss new challenges faced such as requiring description of multiple endpoints, rapid model development, application of machine learning-based analytics, and use of high dimensional and real-world data. Considerations for the continued evolution future of DPMs to serve as community-maintained expert systems are also provided.

Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection (\'converters\'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model\'s ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.