Advance care planning for vulnerable older adults within an Accountable Care Organization: study protocol for the IMPACT randomised controlled trial.

INTRODUCTION: Patients with multimorbidity plus additional impairments (eg, mobility limitations, disability, cognitive impairments or frailty) are at the highest risk for poor healthcare outcomes. Advanced care planning (ACP) provides patients and their surrogates the opportunity to discuss their goals, values and priorities for healthcare-particularly in the context of end-of-life care. ACP discussions promote more person-centred care; however, it is currently underused. There is a tremendous need for systematic, scalable approaches to individualised ACP that promotes patient and family engagement. Here we describe the study protocol for a randomised effectiveness trial of a nurse navigator and informatics intervention designed to improve the documentation and quality of ACP discussions. METHODS AND ANALYSIS: This is a randomised, pragmatic, effectiveness trial; patients aged 65 years and older who have multimorbidity plus impairments in either physical function (eg, mobility limitations or disability) or cognition, and/or frailty within an affiliated Accountable Care Organization were eligible. The electronic health record was used to develop an automatic prescreening system for eligible patients (n=765) and participants were randomised in a 1:1 ratio to either the nurse navigator-led ACP pathway or usual care. Our primary outcomes are documentation of ACP discussions within the EHR along with the quality of ACP discussions. Secondary outcomes include a broad range of ACP actions (eg, usage of ACP billing codes, choosing a surrogate decision-maker and advance directive documentation). Outcomes will be measured over 12 months of follow-up. ETHICS AND DISSEMINATION: This study has been approved by the appropriate Institutional Review Boards and is guided by input from patient and clinical advisory boards. The results of this study will inform a scalable solution to ACP discussions throughout our healthcare system and statewide. TRIALS REGISTRATION NUMBER: NCT03609658.

Immunogenetic influences on acquisition of HIV-1 infection: consensus findings from two African cohorts point to an enhancer element in IL19 (1q32.2).

Numerous reports have suggested that immunogenetic factors may influence human immunodeficiency virus (HIV)-1 acquisition, yet replicated findings that translate between study cohorts remain elusive. Our work aimed to test several hypotheses about genetic variants within the IL10-IL24 gene cluster that encodes interleukin (IL)-10, IL-19, IL-20 and IL-24. In aggregated data from 515 Rwandans and 762 Zambians with up to 12 years of follow-up, 190 single-nucleotide polymorphisms passed quality control procedures. When HIV-1-exposed seronegative subjects (n=486) were compared with newly seroconverted individuals (n=313) and seroprevalent subjects (n=478) who were already infected at enrollment, rs12407485 (G>A) in IL19 showed a robust association signal in adjusted logistic regression models (odds ratio=0.64, P=1.7 × 10(-4) and q=0.033). Sensitivity analyses demonstrated that (i) results from both cohorts and subgroups within each cohort were highly consistent; (ii) verification of HIV-1 infection status after enrollment was critical; and (iii) supporting evidence was readily obtained from Cox proportional hazards models. Data from public databases indicate that rs12407485 is part of an enhancer element for three transcription factors. Overall, these findings suggest that molecular features at the IL19 locus may modestly alter the establishment of HIV-1 infection.

Obesity and mortality: are the risks declining? Evidence from multiple prospective studies in the United States.

We evaluated whether the obesity-associated years of life lost (YLL) have decreased over calendar time. We implemented a meta-analysis including only studies with two or more serial body mass index (BMI) assessments at different calendar years. For each BMI category (normal weight: BMI 18.5 to <25 [reference]; overweight: BMI 25 to <30; grade 1 obesity: BMI 30 to <35; and grade 2-3 obesity: BMI ≥ 35), we estimated the YLL change between 1970 and 1990. Because of low sample sizes for African-American, results are reported on Caucasian. Among men aged ≤60 years YLL for grade 1 obesity increased by 0.72 years (P < 0.001) and by 1.02 years (P = 0.01) for grade 2-3 obesity. For men aged >60, YLL for grade 1 obesity decreased by 1.02 years (P < 0.001) and increased by 0.63 years for grade 2-3 obesity (P = 0.63). Among women aged ≤60, YLL for grade 1 obesity decreased by 4.21 years (P < 0.001) and by 4.97 years (P < 0.001) for grade 2-3 obesity. In women aged >60, YLL for grade 1 obesity decreased by 3.98 years (P < 0.001) and by 2.64 years (P = 0.001) for grade 2-3 obesity. Grade 1 obesity's association with decreased longevity has reduced for older Caucasian men. For Caucasian women, there is evidence of a decline in the obesity YLL association across all ages.

Host genetics and immune control of HIV-1 infection: fine mapping for the extended human MHC region in an African cohort.

Multiple major histocompatibility complex (MHC) loci encoding human leukocyte antigens (HLA) have allelic variants unequivocally associated with differential immune control of HIV-1 infection. Fine mapping based on single nucleotide polymorphisms (SNPs) in the extended MHC (xMHC) region is expected to reveal causal or novel factors and to justify a search for functional mechanisms. We have tested the utility of a custom fine-mapping platform (the ImmunoChip) for 172 HIV-1 seroconverters (SCs) and 449 seroprevalent individuals (SPs) from Lusaka, Zambia, with a focus on more than 6400 informative xMHC SNPs. When conditioned on HLA and nongenetic factors previously associated with HIV-1 viral load (VL) in the study cohort, penalized approaches (HyperLasso models) identified an intergenic SNP (rs3094626 between RPP21 and HLA-E) and an intronic SNP (rs3134931 in NOTCH4) as novel correlates of early set-point VL in SCs. The minor allele of rs2857114 (downstream from HLA-DOB) was an unfavorable factor in SPs. Joint models based on demographic features, HLA alleles and the newly identified SNP variants could explain 29% and 15% of VL variance in SCs and SPs, respectively. These findings and bioinformatics strongly suggest that both classic and nonclassic MHC genes deserve further investigation, especially in Africans with relatively short haplotype blocks.

Epistasis network centrality analysis yields pathway replication across two GWAS cohorts for bipolar disorder.

Most pathway and gene-set enrichment methods prioritize genes by their main effect and do not account for variation due to interactions in the pathway. A portion of the presumed missing heritability in genome-wide association studies (GWAS) may be accounted for through gene-gene interactions and additive genetic variability. In this study, we prioritize genes for pathway enrichment in GWAS of bipolar disorder (BD) by aggregating gene-gene interaction information with main effect associations through a machine learning (evaporative cooling) feature selection and epistasis network centrality analysis. We validate this approach in a two-stage (discovery/replication) pathway analysis of GWAS of BD. The discovery cohort comes from the Wellcome Trust Case Control Consortium (WTCCC) GWAS of BD, and the replication cohort comes from the National Institute of Mental Health (NIMH) GWAS of BD in European Ancestry individuals. Epistasis network centrality yields replicated enrichment of Cadherin signaling pathway, whose genes have been hypothesized to have an important role in BD pathophysiology but have not demonstrated enrichment in previous analysis. Other enriched pathways include Wnt signaling, circadian rhythm pathway, axon guidance and neuroactive ligand-receptor interaction. In addition to pathway enrichment, the collective network approach elevates the importance of ANK3, DGKH and ODZ4 for BD susceptibility in the WTCCC GWAS, despite their weak single-locus effect in the data. These results provide evidence that numerous small interactions among common alleles may contribute to the diathesis for BD and demonstrate the importance of including information from the network of gene-gene interactions as well as main effects when prioritizing genes for pathway analysis.

Body mass index and mortality rate among Hispanic adults: a pooled analysis of multiple epidemiologic data sets.

OBJECTIVE: To evaluate the association between body mass index (BMI, kg m⁻²) and mortality rate among Hispanic adults. METHODS AND PROCEDURES: Analysis of five data sets (total N=16,798) identified after searching for publicly available, prospective cohort data sets containing relevant information for at least 500 Hispanic respondents (≥18 years at baseline), at least 5 years of mortality follow-up, and measured height and weight. Data sets included the third National Health and Nutrition Examination Survey, the Puerto Rico Heart Health Program (PRHHP), the Hispanic Established Population for Epidemiologic Studies of the Elderly (HEPESE), the San Antonio Heart Study (SAHS) and the Sacramento Area Latino Study on Aging. RESULTS: Cox proportional hazards regression models, adjusting for sex and smoking, were fit within three attained-age strata (18 to younger than 60 years, 60 to younger than 70 years, and 70 years and older). We found that underweight was associated with elevated mortality rate for all age groups in the PRHHP (hazard ratios [HRs]=1.38-1.60) and the SAHS (HRs=1.88-2.51). Overweight (HRs=0.38 and 0.84) and obesity grade 2-3 (HRs=0.75 and 0.60) associated with reduced mortality rate in the HEPESE dataset for those in the 60 to younger than 70 years, and 70 years and older attained-age strata. Weighted estimates combining the HRs across the data sets revealed a similar pattern. CONCLUSION: Among Hispanic adults, there was no clear evidence that overweight and obesity associate with elevated mortality rate.

The role of HLA-DR-DQ haplotypes in variable antibody responses to anthrax vaccine adsorbed.

Host genetic variation, particularly within the human leukocyte antigen (HLA) loci, reportedly mediates heterogeneity in immune response to certain vaccines; however, no large study of genetic determinants of anthrax vaccine response has been described. We searched for associations between the immunoglobulin G antibody to protective antigen (AbPA) response to Anthrax Vaccine Adsorbed (AVA) in humans, and polymorphisms at HLA class I (HLA-A, -B, and -C) and class II (HLA-DRB1, -DQA1, -DQB1, -DPB1) loci. The study included 794 European-Americans and 200 African-Americans participating in a 43-month, double-blind and placebo-controlled clinical trial of AVA (clinicaltrials.gov identifier NCT00119067). Among European-Americans, genes from tightly linked HLA-DRB1, -DQA1, -DQB1 haplotypes displayed significant overall associations with longitudinal variation in AbPA levels at 4, 8, 26 and 30 weeks from baseline in response to vaccination with three or four doses of AVA (global P=6.53 × 10(-4)). In particular, carriage of the DRB1-DQA1-DQB1 haplotypes (*)1501-(*)0102-(*)0602 (P=1.17 × 10(-5)), (*)0101-(*)0101-(*)0501 (P=0.009) and (*)0102-(*)0101-(*)0501 (P=0.006) was associated with significantly lower AbPA levels. In carriers of two copies of these haplotypes, lower AbPA levels persisted following subsequent vaccinations. No significant associations were observed amongst African-Americans or for any HLA class I allele/haplotype. Further studies will be required to replicate these findings and to explore the role of host genetic variation outside of the HLA region.

Use of self-reported height and weight biases the body mass index-mortality association.

BACKGROUND: Many large-scale epidemiological data sources used to evaluate the body mass index (BMI: kg/m(2)) mortality association have relied on BMI derived from self-reported height and weight. Although measured BMI (BMI(M)) and self-reported BMI (BMI(SR)) correlate highly, self-reports are systematically biased. OBJECTIVE: To rigorously examine how self-reporting bias influences the association between BMI and mortality rate. SUBJECTS: Samples representing the US non-institutionalized civilian population. DESIGN AND METHODS: National Health and Nutrition Examination Survey data (NHANES II: 1976-80; NHANES III: 1988-94) contain BMI(M) and BMI(SR). We applied Cox regression to estimate mortality hazard ratios (HRs) for BMI(M) and BMI(SR) categories, respectively, and compared results. We similarly analyzed subgroups of ostensibly healthy never-smokers. RESULTS: Misclassification by BMI(SR) among the underweight and obesity ranged from 30-40% despite high correlations between BMI(M) and BMI(SR) (r>0.9). The reporting bias was moderately correlated with BMI(M) (r>0.35), but not BMI(SR) (r<0.15). Analyses using BMI(SR) failed to detect six of eight significant mortality HRs detected by BMI(M). Significantly biased HRs were detected in the NHANES II full data set (χ(2)=12.49; P=0.01) and healthy subgroup (χ(2)=9.93; P=0.04), but not in the NHANES III full data set (χ(2)=5.63; P=0.23) or healthy subgroup (χ(2)=1.52; P=0.82). CONCLUSIONS: BMI(SR) should not be treated as interchangeable with BMI(M) in BMI mortality analyses. Bias and inconsistency introduced by using BMI(SR) in place of BMI(M) in BMI mortality estimation and hypothesis tests may account for important discrepancies in published findings.

Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine.

The variation in antibody response to vaccination likely involves small contributions of numerous genetic variants, such as single-nucleotide polymorphisms (SNPs), which interact in gene networks and pathways. To accumulate the bits of genetic information relevant to the phenotype that are distributed throughout the interaction network, we develop a network eigenvector centrality algorithm (SNPrank) that is sensitive to the weak main effects, gene-gene interactions and small higher-order interactions through hub effects. Analogous to Google PageRank, we interpret the algorithm as the simulation of a random SNP surfer (RSS) that accumulates bits of information in the network through a dynamic probabilistic Markov chain. The transition matrix for the RSS is based on a data-driven genetic association interaction network (GAIN), the nodes of which are SNPs weighted by the main-effect strength and edges weighted by the gene-gene interaction strength. We apply SNPrank to a GAIN analysis of a candidate-gene association study on human immune response to smallpox vaccine. SNPrank implicates a SNP in the retinoid X receptor α (RXRA) gene through a network interaction effect on antibody response. This vitamin A- and D-signaling mediator has been previously implicated in human immune responses, although it would be neglected in a standard analysis because its significance is unremarkable outside the context of its network centrality. This work suggests SNPrank to be a powerful method for identifying network effects in genetic association data and reveals a potential vitamin regulation network association with antibody response.