Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Systematic review of economic aspects of alternative modes of delivery

Objective To carry out a systematic review of the literature relating to economic aspects of alternative modes of delivery. Methods A comprehensive literature search of the years 1990–1999 was conducted of electronic and non-electronic sources using a tested search strategy. Papers considered to contain useful cost or resource use data were read in full and classified according to their relevance to the review and their methodological quality. Relevant cost and resource use data were converted to £ sterling and inflated to 1998-1999 price levels. Results The literature search resulted in 975 papers, 49 of which met criteria for the review. Thirty-two papers were from the USA where the organisation, structure and costs of health care are significantly different from that of other industrialised countries. The aggregate costs of different modes of delivery reported in these American studies were between four and five times higher than costs reported in other studies. The majority of included studies were of poor quality. Data from the better quality studies demonstrated that caesarean section costs a health service substantially more than other modes of delivery. The range of costs of an uncomplicated vaginal delivery were £629-£1298 compared with £1238-£3551 for a caesarean section. However, papers have so far only considered short term health service costs. Conclusions Research is required to estimate the cost and resource use attributable to alternative modes of delivery. Future research should investigate the long term health service costs and the costs that arise outside the health service which are likely to vary according to mode of delivery