Effect of selection of censoring times on survival analysis estimation of disease incidence and association with risk factors

In longitudinal cohort studies, potential risk factors are measured at baseline, subjects are followed over time, and disease endpoints are ascertained via extensive surveillance. Individual follow-up time is from baseline to the event, if one is observed during the study period. Follow-up time is censored for subjects who are not observed to have the event during the study period, at the end of the study period for subjects who remain event-free, but during the study period for subjects who leave the study early by choice or by mortality, or whose last evaluation was before the end of the study. Survival analytic techniques are unique in that the unit of analysis is not the individual but the person-time contributed by the individual. Surveillance in longitudinal studies is generally quite rigorous. Subjects are examined in waves and their event status is ascertained. Surveillance continues between waves, and events come to the attention of the investigator. If there is a long time between waves, analyses can be conducted on all available data, with non-events censored early at the last examination and events followed beyond the general examination to the incident event. Motivated by analyses using the Framingham Heart Study (FHS) with cardiovascular endpoints, we consider four censoring methods for non-events and evaluate their impact on estimates of incidence, and on tests of association between risk factors and incidence. We further investigate the impact of early censoring of non-events (as compared to events) under various scenarios with respect to incidence estimation, robustness, and power using a simulation study of Weibull survival models over a range of sample sizes and distribution parameters. Our FHS and simulation investigations show early censoring of non-events causes over estimation of incidence, particularly when the baseline incidence is low. Early censoring of non-events did not affect the robustness of the Wald test [Ho: Hazard Ratio (HR) =1]. However, in both the FHS and over the range of simulation scenarios, under early censoring of non-events, estimates of HR were closer to the null (1.0), and the power to detect associations with risk factors was markedly reduced

Elevated Amyloid-β and Tau Levels in the Brain are Associated with a Reduced Abundance of Neuroprotective Gut Bacteria

Background: Recent research suggests that differences in the gut microbiome composition may contribute to the pathogenesis of neurological disorders, including Alzheimer\u27s disease (AD). Animal studies have shown that fecal microbiota transplantation reduces amyloid plaques in mouse AD models. However, whether the buildup of Aβ and tau deposits in the brain are associated with shifts in the human gut microbiota composition is understudied. Method: We used stool specimens and neuropathological measures from 140 middle-aged individuals (Table 1: mean age 56, 54% Female) from the Framingham Heart Study (FHS) to assess the link between the gut microbiome composition and Aβ Positron Emission Tomography (Aβ-PET) in a global composite brain measure, and tau-PET deposits in the rhinal cortex and the inferior temporal cortex. We quantified gut microbiome composition using 16S rRNA sequencing. We performed multivariable association and differential abundance analyses, adjusting for age, sex, body mass index, and other confounders. Result: Multivariable association results (Figure 1) indicated significant associations (adjusted p-value \u3c 0.001) between both Aβ-PET and tau-PET levels with abundance of genera Butyricicoccus and Ruminococcus. Moreover, differential abundance analysis (Figure 2) showed that these bacteria have lower than expected abundance in individuals with elevated Aβ-PET and tau-PET measures (Aβ-PET, Ruminococcus: OR = 0.89, [0.88, 0.91]; Butyricicoccus: OR = 0.77, [0.72, 0.81]); (tau-PET in the rhinal cortex: Ruminococcus: OR = 0.82, [0.8, 0.83]; Butyricicoccus: OR = 0.91 [0.88, 0.94]); (tau-PET in the inferotemporal cortex:, Ruminococcus: OR = 0.79 [0.78, 0.81]; Butyricicoccus: OR = 0.83 [0.81, 0.86]). Conversely, we observed an increased abundance of genera Cytophaga (tau-PET in the rhinal cortex, OR = 1.78, [1.15, 2.75]) and Alistipes (tau-PET in the rhinal cortex, OR = 1.19, [1.17, 1.22]) in individuals with high Aβ-PET and tau-PET levels. Finally, functional analysis showed that Butyricicoccus and Ruminococcus are butyrate-producing bacteria harboring neuroprotective effects. Conclusion: We showed that elevated measures of Aβ-PET and tau-PET in the rhinal and the inferior temporal cortex are associated with a reduced abundance of butyrate-producing Butyricicoccus and Ruminococcus in the gut of middle-aged individuals from the FHS. As these bacteria harbor neuroprotective effects, further studies are needed to elucidate underlying mechanisms and assess their therapeutic potential

Poor cognition is associated with increased abundance of Alistipes and decreased abundance of Clostridium genera in the gut

Background: Brain and gut health are intricately connected via the gut-microbiota-brain axis. Studies have shown that gut dysbiosis is associated with neurodegenerative diseases, including Alzheimer’s disease. However, how cognitive changes affects the gut microbiome structure is currently understudied. We aimed to assess the association between the gut microbiome and global cognitive scores in the Framingham Heart Study (FHS). Method: Our sample included 1,014 participants (mean age 52, 55% female) of the third generation FHS cohort with available stool samples, cognitive assessments, and no history of dementia or stroke (Table 1).We quantified the gut microbiome composition using 16S rRNA sequencing and performed multivariable association and differential abundance analyses, adjusting for age, sex, education, BMI, and other confounders. The global cognitive score (GCS) was built using neuropsychological assessments of four cognitive domains: Executive function (trails-making B); Processing speed (visual reproduction immediate and delayed); Language (similarity test); and Memory (logical memory immediate and delayed). Participants were additionally stratified by GCS with lower and higher scores indicating poor and normal cognition, respectively. Result: Our results (Figure 1) showed that individuals with poor cognition have a decreased abundance of genera Clostridium (OR = 0.69, 95% CI [0.55, 0.86]) and Ruminococcus (0.93, [0.93, 0.94]). Meanwhile, the genus Alistipes, previously connected to anxiety, chronic fatigue syndrome, depression, and hypertension, was more abundant (1.06, [1.05, 1.06]) in the poor cognition group. Moreover, the genus Pseudobutyrivibrio, a butyrate-producing bacteria from the rumen, was also found to be highly abundant (1.12, [1.11, 1.14]) in the poor cognition compared to normal. Finally, there was no difference in alpha and beta diversity between cognitive groups (Figure 2). Conclusion: Our study suggests that the abundance of several genera, including Pseudobutyrivibrio, Alistipes, Ruminococcus, and Clostridium is associated with cognition in middle-age. Clostridium was previously proposed as novel probiotics for human health, and increasing its abundance was viewed as an effective strategy to regulate and maintain the homeostasis of the gut microbiota. As all these bacteria have neuroprotective effects, manipulating their abundance through diet and pre/pro-biotics could be a research path for preserving global cognitive function in the future

DNA Methylation Signatures of Depressive Symptoms in Middle-aged and Elderly Persons:Meta-analysis of Multiethnic Epigenome-wide Studies

IMPORTANCE Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers.OBJECTIVE To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood.DESIGN, SETTING, AND PARTICIPANTS To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts.MAIN OUTCOMES AND MEASURES Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire.RESULTS The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%) women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 x 10(-)(08); n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 x 10(-09); n = 11256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 x 10(-)(08); n = 11256; chromosome = 15q261). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 x 10(-03)) and of ARHGEF3 in fibroblasts (effect. -0.48; P = 9.8 x 10(-)(04) ) was associated with major depression.CONCLUSIONS AND RELEVANCE This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects. (C) 2018 American Medical Association. All lights reserved

Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife

Background and objectivesDiet may be a key contributor to brain health in midlife. In particular, Omega-3 fatty acids have been related to better neurological outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) Omega-3 fatty acid concentrations with MRI and cognitive markers of brain aging in a community-based sample of predominantly middle-aged adults, and further explore effect modification by APOE genotype.MethodsWe included participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study attending their second examination. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations were measured from RBC using gas chromatography, and the Omega-3 index was calculated as EPA + DHA. We used linear regression models to relate Omega-3 fatty acid concentrations to brain MRI measures (i.e., total brain, total gray matter, hippocampal, and white matter hyperintensity volumes) and cognitive function (i.e., episodic memory, processing speed, executive function, and abstract reasoning) adjusting for potential confounders. We further tested for interactions between omega-3 fatty acid levels and APOE genotype (e4 carrier vs. non-carrier) on MRI and cognitive outcomes.ResultsWe included 2,183 dementia- and stroke-free participants (mean age 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ±0.001, p=0.04), and better abstract reasoning (0.17 ±0.07, p=0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 non-carriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all Omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers.DiscussionOur results, albeit exploratory, suggest that higher Omega-3 fatty acid concentrations are related to better brain structure and cognitive function in a predominantly middle-aged cohort free of clinical dementia. These associations differed by APOE genotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-age populations are warranted to confirm these findings