DunedinPACE, a DNA methylation biomarker of the pace of aging

Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al. 2020). Here we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).Methods: We used data from the Dunedin Study 1972-3 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets.Results: DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge.Conclusions: DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience.Funding: This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.

Cause of Death, Mortality and Occult Blood in Colorectal Cancer Screening

Fecal hemoglobin (f-Hb) detected by the guaiac fecal occult blood test (gFOBT) may be associated with mortality and cause of death in colorectal cancer (CRC) screening participants. We investigated this association in a randomly selected population of 20,694 participants followed for 33 years. We followed participants from the start of the Hemoccult-II CRC trial in 1985–1986 until December 2018. Data on mortality, cause of death and covariates were retrieved using Danish national registers. We conducted multivariable Cox regressions with time-varying exposure, reporting results as crude and adjusted hazard ratios (aHRs). We identified 1766 patients with at least one positive gFOBT, 946 of whom died in the study period. Most gFOBT-positive participants (93.23%) died of diseases unrelated to CRC and showed higher non-CRC mortality than gFOBT-negative participants (aHR: 1.20, 95% CI 1.10–1.30). Positive gFOBT participants displayed a modest increase in all-cause (aHR: 1.28, 95% CI: 1.18–1.38), CRC (aHR: 4.07, 95% CI: 3.00–5.56), cardiovascular (aHR: 1.22, 95% CI: 1.07–1.39) and endocrine and hematological mortality (aHR: 1.58, 95% CI: 1.19–2.10). In conclusion, we observed an association between positive gFOBT, cause of death and mortality. The presence of f-Hb in the gFOBT might indicate the presence of systemic diseases.

Predictors of the development of hepatorenal syndrome

Objective. To identify the predictors of the development of hepatorenal syndrome in patients with liver cirrhosis.Materials and methods. We analyzed the medical records of 79 patients diagnosed with liver cirrhosis. The laboratory research included general and biochemical blood tests. The general blood test measured erythrocyte and leukocyte counts. The biochemical blood test measured the content of ALT (U/L), AST (E/L), total bilirubin (μmol/L), direct bilirubin (μmol/L), indirect bilirubin (μmol/L), alkaline phosphatase (U/L), albumin (g/L), urea (mmol/L), creatinine (mmol/L), cholesterol (mmol/L).Viral hepatitis markers were determined for all the patients.Results. The predictors of the development of hepatorenal syndrome were identified: increased leukocyte count, increased total and indirect bilirubin levels, urea level and decreased erythrocyte count and albumin level. The most specific predictors were the amount of indirect bilirubin (98 %) and the content of albumin in the serum (89.8 %), and the most sensitive predictors were AST (96.7 %) and the content of red blood cells and creatinine (73.3 %).Conclusion. The most significant predictors of the development obtained will contribute to the diagnosis of the development of hepatorenal syndrome in patients with liver cirrhosis.

DIAGNOSTIC ROLE OF DIFFUSION-WEIGHTED IMAGE OF THE LIVER WITH MAGNETIC RESONANCE IMAGING IN PREDICTING ABSTINENCE DISORDERS IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

Objective. To assess the diagnostic role of diffusion-weighted images of the liver with magnetic resonance imaging in predicting abstinence disorders in patients with alcoholic liver disease. Methods. A total of 122 patients with ALD aged 48±5.4 years were examined. The survey algorithm we used included: performing liver DWI with MRI (n=122) with b-value values of 100/600/1000, ultrasound of abdominal organs with clinical elastography – 97 (80%) patients. Trepan liver biopsy was chosen as a reference method (n=64). Results. The patients were monitored for 2.5 years. The terms of follow-up were selected individually, depending on the results of clinical and laboratory research methods. A high correlation was established (r=0.879), when comparing clinical elastography and quantitative indicators of DWI of the liver, at admission and during dynamic observation of patients, also at the middle level, the data obtained correlated with the results of trephine biopsy of the liver (r=0.721). After 3 months, 6 (15%) of 40 patients showed normalization of biochemical blood test parameters with no diffusion restriction according to the results of DWI of the liver. Based on the results obtained, a high correlation was noted between changes in the biochemical blood test and MRI data in the DWI mode. After 9 months of follow-up, according to DWI data, 34 patients showed persistence of cytolysis syndrome and limited diffusion on DWI of the liver. After collecting an additional history and clarifying the details of the lifestyle of the patients' relatives, it was found that these patients continued to consume alcoholic beverages against the background of the received treatment, which was manifested by the presence of diffusion restriction on MRI in the DWI mode, which was a magnetic resonance sign of the presence of inflammatory processes in the structure of the parenchyma liver. After 12 months, positive dynamics – the absence of diffusion restriction according to the results of DWI of the liver was noted in 34 patients, which indicates the effectiveness of using the qualitative characteristics of DWI of the liver to assess the violation of the abstinence regimen (AUROC=0.906 (95% CI 0.872-0.916)). But in 16 (13%) patients from this group, changes in the biochemical blood test were noted, but no diffusion limitation was noted according to the DWI of the liver. Patients (n=16) underwent a correction of the received treatment – after 1 month there was a positive trend. There was a correlation of quantitative parameters of DWI of the liver with clinical forms of ALD, regardless of the presence or absence of diffusion restriction (r=0.936). Next, we assessed the prognostic and diagnostic significance of the developed criteria for DWI of the liver for patients with ALD on admission. The results of the study indicated the effectiveness of using the diagnostic and prognostic model of MRI in the DWI mode for patients with ALD on admission and in dynamic observation. Conclusions. 1. A high correlation was found between the quantitative parameters of DWI of the liver and clinical elastography (r=0.879) at admission and follow-up. Average correlation relationship of DWI of the liver with the results of trephine biopsy of the liver in patients with ALD on admission and follow-up (r=0.721). There was a high correlation between the results of DWI of the liver on MRI with the data of clinical and laboratory parameters in dynamic observation of patients with ALD: no diffusion limitation – positive (r=0.887); yes – negative (r=0.887). The high prognostic and diagnostic value of DWI of the liver in assessing the violation of the abstinence regimen in patients with ALD was established (AUROC=0.906 (95% CI 0.872-0.916)). Prognostic and diagnostic criteria for liver DWI on MRI in patients with ALD at admission: qualitative characteristic – AUROC=0.846 (95% CI 0.811-0.862), quantitative characteristic – AUROC=0.909 (95% CI 0.879-0.912); with dynamic observation: qualitative characteristic – AUROC=0.949 (95% CI 0.907-0.965), quantitative characteristic – AUROC=0.917 (95% CI 0.876-0.932).