Delineating genotype and parent-of-origin effect on the phenotype in MSH6-associated Lynch syndrome.

BACKGROUND: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants. PATIENTS AND METHODS: A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC). RESULTS: No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77-1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43-1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46-0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52-1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65-1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64-1.19). DISCUSSION AND CONCLUSION: No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

Clarifying the biological and statistical assumptions of cross-sectional biological age predictors: an elaborate illustration using synthetic and real data.

BACKGROUND: There is divergence in the rate at which people age. The concept of biological age is postulated to capture this variability, and hence to better represent an individual's true global physiological state than chronological age. Biological age predictors are often generated based on cross-sectional data, using biochemical or molecular markers as predictor variables. It is assumed that the difference between chronological and predicted biological age is informative of one's chronological age-independent aging divergence ∆. METHODS: We investigated the statistical assumptions underlying the most popular cross-sectional biological age predictors, based on multiple linear regression, the Klemera-Doubal method or principal component analysis. We used synthetic and real data to illustrate the consequences if this assumption does not hold. RESULTS: The most popular cross-sectional biological age predictors all use the same strong underlying assumption, namely that a candidate marker of aging's association with chronological age is directly informative of its association with the aging rate ∆. We called this the identical-association assumption and proved that it is untestable in a cross-sectional setting. If this assumption does not hold, weights assigned to candidate markers of aging are uninformative, and no more signal may be captured than if markers would have been assigned weights at random. CONCLUSIONS: Cross-sectional methods for predicting biological age commonly use the untestable identical-association assumption, which previous literature in the field had never explicitly acknowledged. These methods have inherent limitations and may provide uninformative results, highlighting the importance of researchers exercising caution in the development and interpretation of cross-sectional biological age predictors.

The AccelerAge framework: a new statistical approach to predict biological age based on time-to-event data.

Aging is a multifaceted and intricate physiological process characterized by a gradual decline in functional capacity, leading to increased susceptibility to diseases and mortality. While chronological age serves as a strong risk factor for age-related health conditions, considerable heterogeneity exists in the aging trajectories of individuals, suggesting that biological age may provide a more nuanced understanding of the aging process. However, the concept of biological age lacks a clear operationalization, leading to the development of various biological age predictors without a solid statistical foundation. This paper addresses these limitations by proposing a comprehensive operationalization of biological age, introducing the "AccelerAge" framework for predicting biological age, and introducing previously underutilized evaluation measures for assessing the performance of biological age predictors. The AccelerAge framework, based on Accelerated Failure Time (AFT) models, directly models the effect of candidate predictors of aging on an individual's survival time, aligning with the prevalent metaphor of aging as a clock. We compare predictors based on the AccelerAge framework to a predictor based on the GrimAge predictor, which is considered one of the best-performing biological age predictors, using simulated data as well as data from the UK Biobank and the Leiden Longevity Study. Our approach seeks to establish a robust statistical foundation for biological age clocks, enabling a more accurate and interpretable assessment of an individual's aging status.

Physical activity and fiber intake beneficial for muscle mass and strength preservation during aging: A comprehensive cross-sectional study in the UK biobank cohort.

BACKGROUND: Aging triggers intricate physiological changes, particularly in whole-body fat-free mass (FFM) and handgrip strength, affecting overall health and independence. Despite existing research, the broader significance of how muscle health is affected by the intricate interplay of lifestyle factors simultaneously during aging needs more exploration. This study aims to examine how nutrition, physical activity, and sleep impact on FFM and handgrip strength in middle-aged men and women, facilitating future personalized recommendations for preserving muscle health. METHODS: The cross-sectional analysis of the UK Biobank involved 45,984 individuals (54 % women) aged 40-70 years with a complete dataset. Multiple linear regression explored determinants of FFM and handgrip strength, considering traditional, socio-demographics, medication use and smoking as covariates, with sex and age (younger and older than 55 years) stratifications. RESULTS: In older men and women, higher physical activity beneficially affect both FFM (respectively Β = 3.36 × 10-3, p-value = 1.66 × 10-3; Β = 2.52 × 10-3, p-value = 3.57 × 10-4) and handgrip strength (Β = 6.05 × 10-3, p-value = 7.99 × 10-5, Β = 8.98 × 10-3, p-value = 2.95 × 10-15). Similar results were found in fiber intake for FFM in older men and women (respectively B = 3.00 × 10-2, p-value = 2.76 × 10-5; B = 2.68 × 10-2, p-value = 1.78 × 10-9) and handgrip strength (Β = 3.27 × 10-2, p-value = 1.40 × 10-3; Β = 3.12 × 10-2, p-value = 1.34 × 10-5). Other lifestyle factors influence FFM and handgrip strength differently. Key determinants influencing handgrip strength included higher protein intake, lower water intake, higher alcohol intake, and extended sleep duration whereas mainly higher water intake is associated with higher FFM. CONCLUSIONS: In both men and women, the main factors associated with FFM and handgrip strength are physical activity and fiber intake, which may underlie a connection between gut and muscle health. Given the observed complexity of muscle health in the age and sex strata, further longitudinal research is needed to provide personalized lifestyle recommendations.

Prevalence of Juvenile-Onset and Pediatric Huntington's Disease and Their Availability and Ability to Participate in Trials: A Dutch Population and Enroll-HD Observational Study.

Background: Juvenile-onset Huntington's disease (JHD) represents 1-5% of Huntington's disease (HD) patients, with onset before the age of 21. Pediatric HD (PHD) relates to a proportion of JHD patients that is still under 18 years of age. So far, both populations have been excluded from interventional trials. Objective: Describe the prevalence and incidence of JHD and PHD in the Netherlands and explore their ability to participate in interventional trials. Methods: The prevalence and incidence of PHD and JHD patients in the Netherlands were analyzed. In addition, we explored proportions of JHD patients diagnosed at pediatric versus adult age, their diagnostic delay, and functional and modelled (CAP100) disease stage in JHD and adult-onset HD patients at diagnosis. Results: The prevalence of JHD and PHD relative to the total manifest HD population in January 2024 was between 0.84-1.25% and 0.09-0.14% respectively. The mean incidence of JHD patients being diagnosed was between 0.85-1.28 per 1000 patient years and of PHD 0.14 per 1.000.000 under-aged person years. 55% of JHD cases received a clinical diagnosis on adult age. At diagnosis, the majority of JHD patients was functionally compromised and adolescent-onset JHD patients were significantly less independent compared to adult-onset HD patients. Conclusions: In the Netherlands, the epidemiology of JHD and PHD is lower than previously suggested. More than half of JHD cases are not eligible for trials in the PHD population. Furthermore, higher functional dependency in JHD patients influences their ability to participate in trials. Lastly, certain UHDRS functional assessments and the CAP100 score do not seem appropriate for this particular group.

Association of NOTCH3 Variant Risk Category With 2-Year Clinical and Radiologic Small Vessel Disease Progression in Patients With CADASIL.

BACKGROUND AND OBJECTIVES: Pathogenic variants in NOTCH3 are the main cause of hereditary cerebral small vessel disease (SVD). SVD-associated NOTCH3 variants have recently been categorized into high risk (HR), moderate risk (MR), or low risk (LR) for developing early-onset severe SVD. The most severe NOTCH3-associated SVD phenotype is also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to investigate whether NOTCH3 variant risk category is associated with 2-year progression rate of SVD clinical and neuroimaging outcomes in CADASIL. METHODS: A single-center prospective 2-year follow-up study was performed of patients with CADASIL. Clinical outcomes were incident stroke, disability (modified Rankin Scale), and executive function (Trail Making Test B given A t-scores). Neuroimaging outcomes were mean skeletonized mean diffusivity (MSMD), normalized white matter hyperintensity volume (nWMHv), normalized lacune volume (nLV), and brain parenchymal fraction (BPF). Cox regression and mixed-effect models, adjusted for age, sex, and cardiovascular risk factors, were used to study 2-year changes in outcomes and differences in disease progression between patients with HR-NOTCH3 and MR-NOTCH3 variants. RESULTS: One hundred sixty-two patients with HR (n = 90), MR (n = 67), and LR (n = 5) NOTCH3 variants were included. For the entire cohort, there was 2-year mean progression for MSMD (ß = 0.20, 95% CI 0.17-0.23, p = 7.0 × 10-24), nLV (ß = 0.13, 95% CI 0.080-0.19, p = 2.1 × 10-6), nWMHv (ß = 0.092, 95% CI 0.075-0.11, p = 8.8 × 10-20), and BPF (ß = -0.22, 95% CI -0.26 to -0.19, p = 3.2 × 10-22), as well as an increase in disability (p = 0.002) and decline of executive function (ß = -0.15, 95% CI -0.30 to -3.4 × 10-5, p = 0.05). The HR-NOTCH3 group had a higher probability of 2-year incident stroke (hazard ratio 4.3, 95% CI 1.4-13.5, p = 0.011), and a higher increase in MSMD (ß = 0.074, 95% CI 0.013-0.14, p = 0.017) and nLV (ß = 0.14, 95% CI 0.034-0.24, p = 0.0089) than the MR-NOTCH3 group. Subgroup analyses showed significant 2-year progression of MSMD in young (n = 17, ß = 0.014, 95% CI 0.0093-0.019, p = 1.4 × 10-5) and premanifest (n = 24, ß = 0.012, 95% CI 0.0082-0.016, p = 1.1 × 10-6) individuals. DISCUSSION: In a trial-sensitive time span of 2 years, we found that patients with HR-NOTCH3 variants have a significantly faster progression of major clinical and neuroimaging outcomes, compared with patients with MR-NOTCH3 variants. This has important implications for clinical trial design and disease prediction and monitoring in the clinic. Moreover, we show that MSMD is a promising outcome measure for trials enrolling premanifest individuals.