Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing

Austin, Thomas R.; McHugh, Caitlin; Brody, Jennifer A.; Bis, Joshua C.; Sitlani, Colleen M.; Bartz, Traci M.; Biggs, Mary L.; Bansal, Nisha; Bůžková, Petra; Carr, Steven A.; deFilippi, Christopher R.; Elkind, Mitchell S.V.; Fink, Howard A; Floyd, James S.; Fohner, Alison E.; Gerszten, Robert E.; Heckbert, Susan R.; Katz, Daniel H.; Kizer, Jorge R.; Lemaître, Rozenn N.; Longstreth, W. T.; McKnight, Barbara; Mei, Hao; Mukamal, Kenneth J.; Newman, Anne B.; Ngo, Debby; Odden, Michelle C.; Vasan, Ramachandran S.; Shojaie, Ali; Simon, Noah; Smith, George Davey; Davies, Neil M; Siscovick, David S.; Sotoodehnia, Nona; Tracy, Russell P.; Wiggins, Kerri L.; Zheng, Jie; Psaty, Bruce M.

doi:10.1007/s10654-022-00888-z

Cited by 13 publications

(17 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Briefly, slow off‐rate modified aptamers (SOMA) were used to target proteins and evaluated relative concentrations of multiple proteins on a single assay and SOMAscan was preferred due to a larger panel size over other platforms at the time of the study. The clinical and analytic validity of the aptamer‐based assay method has been demonstrated in recent reports (Ngo et al, 2016 ) and the high correlation between SOMAscan levels and conventional ELISA‐based measures suggests the platform is comparable to other available methods and particularly well suited for plasma biomarker discovery (Austin et al, 2022 ; Fitzgibbons et al, 2017 ). The SOMAscan technology was used to run the assays in 2020 for CHS (Version 4.0) and in 2011 for FOS (Version 1.1 and 1.3) and, according to the fee for service agreement, provided measures of 1305 plasma proteins in CHS from samples drawn in 1992–1993 (the third examination for the original cohort and first for the African American cohort) and 1373 proteins in FOS from samples drawn in 1991–1995 (the fifth examination).…”

Section: Methodsmentioning

confidence: 96%

“…The median intra‐assay (inter‐assay) coefficient of variation was 3.4% (4.4%) for CHS proteins using quality control samples and <8.2% (7.8%) for FOS proteins using pooled plasma samples. Intraclass correlation coefficient was 0.66 in 100 samples from two examination cycles for CHS and >0.95 for FOS‐blinded duplicate samples (Austin et al, 2022 ; Ngo et al, 2016 ). The values of protein levels were log 2 ‐transformed and standardized (mean = 0, SD = 1) in CHS and were log e ‐transformed and standardized in FOS for this analysis.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Plasma proteomic signature of decline in gait speed and grip strength

et al. 2022

Self Cite

View full text Add to dashboard Cite

The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community‐dwelling adults. We applied an aptamer‐based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992–1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991–1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998–2001) and 8 (2005–2008) in FOS. The associations of individual protein levels (log‐transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed‐effects models. Meta‐analyses were implemented using random‐effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF‐15 (Meta‐analytic p = 1.58 × 10−15), pleiotrophin (1.23 × 10−9), and TIMP‐1 (5.97 × 10−8). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 × 10−7), CDON (2.38 × 10−7), and SMOC1 (7.47 × 10−7). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age‐related functional decline.

show abstract

Section: Methodsmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Plasma proteomic signature of decline in gait speed and grip strength

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…EDTA plasma samples were processed in a standardized fashion, shipped on dry ice to the CHS Core Laboratory, and, after initial storage in −70°C freezers, they have been stored at −80° for the past 20 years. 13 All participants with previously unthawed plasma samples available from the 1992–1993 clinic visit (N = 3,188) underwent plasma proteomics, as part of the CHS Proteomics Ancillary Study, and samples for 3,185 participants passed quality control criteria. 13 The Institutional Review Boards at the University of Washington and each study site approved the study, and all CHS participants provided written informed consent.…”

Section: Methodsmentioning

confidence: 99%

“…13 All participants with previously unthawed plasma samples available from the 1992–1993 clinic visit (N = 3,188) underwent plasma proteomics, as part of the CHS Proteomics Ancillary Study, and samples for 3,185 participants passed quality control criteria. 13 The Institutional Review Boards at the University of Washington and each study site approved the study, and all CHS participants provided written informed consent. Data that are reported in this study are available on reasonable request through the CHS Coordinating Center (CHS-NHLBI.org).…”

Section: Methodsmentioning

confidence: 99%

“…Quality control measures for the SOMAScan analyses for the CHS Proteomics Ancillary Study have been previously described. 13 Incident IS Clinical IS events were adjudicated by an expert events committee, composed of neurologists from the study sites and CHS coordinating center and a neuroradiologist from the imaging reading center. 14 Information provided to the adjudicators included clinical history, examination findings, laboratory reports, and imaging studies.…”

Section: Plasma Protein Quantificationmentioning

confidence: 99%

See 1 more Smart Citation

Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults

et al. 2023

Self Cite

View full text Add to dashboard Cite

Background:Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS).Methods:Eligible CHS participants were free of prevalent stroke and underwent quantification of 1298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-standard deviation increase in the log-2 transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and non-cardioembolic IS as well as proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation.Results:Of 2983 eligible participants, the mean age was 74.3 (± 4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal pro-brain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, P=2.08x10-08) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, P=4.55x10-06) were independently associated with IS risk. These two associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident non-cardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction.Conclusions:In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and non-cardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.

show abstract

Proteomic prediction of incident heart failure and its main subtypes

Emilsson,

Jonsson,

Austin

et al. 2023

European J of Heart Fail

View full text Add to dashboard Cite

AimTo examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF‐associated clinical variables.Methods and resultsIn the prospective population‐based Age, Gene/Environment Susceptibility Reykjavik Study (AGES‐RS), 440 individuals developed HF after their first visit with a median follow‐up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non‐parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre‐established clinical parameters linked to HF. A subset of 8–10 distinct or overlapping serum proteins predicted different future HF outcomes, and C‐statistics were used to assess discrimination, revealing proteins combined with a C‐index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES‐RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N‐terminal pro‐B‐type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study.ConclusionA small number of circulating proteins accurately predicted future HF in the AGES‐RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study.

show abstract

Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing

Cited by 13 publications

References 49 publications

Plasma proteomic signature of decline in gait speed and grip strength

Plasma proteomic signature of decline in gait speed and grip strength

Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults

Proteomic prediction of incident heart failure and its main subtypes

Contact Info

Product

Resources

About