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Sporadic, late-onset, and multistage diseases.

ABSTRACT: Multistage disease processes are often characterized by a linear relationship between the log of incidence rates and the log of age. Examples include sequences of somatic mutations, that can cause cancer, and have recently been linked with a range of non-malignant diseases. Using a Weibull distribution to model diseases that occur through an ordered sequence of stages, and another model where stages can occur in any order, we characterized the age-related onset of disease in UK Biobank data. Despite their different underlying assumptions, both models accurately described the incidence of over 450 diseases, demonstrating that multistage disease processes cannot be inferred from this data alone. The parametric models provided unique insights into age-related disease, that conventional studies of relative risks cannot. The rate at which disease risk increases with age was used to distinguish between "sporadic" diseases, with an initially low and slowly increasing risk, and "late-onset" diseases whose negligible risk when young rapidly increases with age. "Relative aging rates" were introduced to quantify how risk factors modify age-related risk, finding the effective age-at-risk of sporadic diseases is strongly modified by common risk factors. Relative aging rates are ideal for risk-stratification, allowing the identification of ages with equivalent-risk in groups with different exposures. Most importantly, our results suggest that a substantial burden of sporadic diseases can be substantially delayed or avoided by early lifestyle interventions.

SUBMITTER: Webster AJ

PROVIDER: S-EPMC9308562 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDegradation of white matter microstructure has been demonstrated in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). In preparation for clinical trials, ongoing studies are investigating the utility of longitudinal brain imaging for quantification of disease progression. To date only one study has examined sample size calculations based on longitudinal changes in white matter integrity in FTLD.ObjectiveTo quantify longitudinal changes in white matter microstructural integrity in the three canonical subtypes of frontotemporal dementia (FTD) and AD using diffusion tensor imaging (DTI).Methods60 patients with clinical diagnoses of FTD, including 27 with behavioral variant frontotemporal dementia (bvFTD), 14 with non-fluent variant primary progressive aphasia (nfvPPA), and 19 with semantic variant PPA (svPPA), as well as 19 patients with AD and 69 healthy controls were studied. We used a voxel-wise approach to calculate annual rate of change in fractional anisotropy (FA) and mean diffusivity (MD) in each group using two time points approximately one year apart. Mean rates of change in FA and MD in 48 atlas-based regions-of-interest, as well as global measures of cognitive function were used to calculate sample sizes for clinical trials (80% power, alpha of 5%).ResultsAll FTD groups showed statistically significant baseline and longitudinal white matter degeneration, with predominant involvement of frontal tracts in the bvFTD group, frontal and temporal tracts in the PPA groups and posterior tracts in the AD group. Longitudinal change in MD yielded a larger number of regions with sample sizes below 100 participants per therapeutic arm in comparison with FA. SvPPA had the smallest sample size based on change in MD in the fornix (n = 41 participants per study arm to detect a 40% effect of drug), and nfvPPA and AD had their smallest sample sizes based on rate of change in MD within the left superior longitudinal fasciculus (n = 49 for nfvPPA, and n = 23 for AD). BvFTD generally showed the largest sample size estimates (minimum n = 140 based on MD in the corpus callosum). The corpus callosum appeared to be the best region for a potential study that would include all FTD subtypes. Change in global measure of functional status (CDR box score) yielded the smallest sample size for bvFTD (n = 71), but clinical measures were inferior to white matter change for the other groups.ConclusionsAll three of the canonical subtypes of FTD are associated with significant change in white matter integrity over one year. These changes are consistent enough that drug effects in future clinical trials could be detected with relatively small numbers of participants. While there are some differences in regions of change across groups, the genu of the corpus callosum is a region that could be used to track progression in studies that include all subtypes.

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Sporadic, late-onset, and multistage diseases.

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