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Study Description

The Cleveland Family Study is the largest family-based study of sleep apnea world-wide, consisting of 2284 individuals (46% African American) from 361 families studied on up to 4 occasions over a period of 16 years. The study was begun in 1990 with the initial aims of quantifying the familial aggregation of sleep apnea. NIH renewals provided expansion of the original cohort (including increased minority recruitment) and longitudinal follow-up, with the last exam occurring in February 2006. Index probands (n=275) were recruited from 3 area hospital sleep labs if they had a confirmed diagnosis of sleep apnea and at least 2 first-degree relatives available to be studied. In the first 5 years of the study, neighborhood control probands (n=87) with at least 2 living relatives available for study were selected at random from a list provided by the index family and also studied. All available first degree relatives and spouses of the case and control probands also were recruited. Second-degree relatives, including half-sibs, aunts, uncles and grandparents, were also included if they lived near the first degree relatives (cases or controls), or if the family had been found to have two or more relatives with sleep apnea. Blood was sampled and DNA isolated for participants seen in the last two exam cycles (n=1447). The sample, which is enriched with individuals with sleep apnea, also contains a high prevalence of individuals with sleep apnea-related traits, including: obesity, impaired glucose tolerance, and HTN.

Phenotyping data have been collected over 4 exam cycles, each occurring ~every 4 years. The last three exams targeted all subjects who had been studied at earlier exams, as well as new minority families and family members of previously studied probands who had been unavailable at prior exams. Data from one, two, three and four visits are available for 412, 630, 329 and 67, participants, respectively. In the first 3 exams, participants underwent overnight in-home sleep studies, allowing determination of the number and duration of hypopneas and apneas, sleep period, heart rate, and oxygen saturation levels; anthropometry (weight, height, and waist, hip, and neck circumferences); resting blood pressure; spirometry; standardized questionnaire evaluation of symptoms, medications, sleep patterns, quality of life, daytime sleepiness measures and health history; venipuncture and measurement of total and HDL cholesterol. The 4th exam (2001-2006) was designed to collect more detailed measurements of sleep, metabolic and CVD phenotypes and included measurement of state-of-the-art polysomnography, with both collection of blood and measurement of blood pressure before and after sleep, and anthropometry, upper airway assessments, spirometry, exhaled nitric oxide, and ECG performed the morning after the sleep study.

Data have been collected by trained research assistants or GCRC nurses following written Manuals of Procedures who were certified following standard approaches for each study procedure. Ongoing data quality, with assessment of within or between individual drift, has been monitored on an ongoing basis, using statistical techniques as well as regular re-certification procedures. Between and within scorer reliabilities for key sleep apnea indices have been excellent, with intra-class correlation coefficients (ICCs) exceeding 0.92 for the apnea-hypopnea index (AHI). Sleep staging, assessed with epoch specific comparisons, also demonstrate excellent reliability for stage identification (kappas>0.82). There has been no evidence of significant time trends-between or within scorers- for the AHI variables. We also have evaluated the night-to-night variability of the AHI and other sleep variables in 91 subjects, with each measurement made 1-3 months apart. There is high night to night consistency for the AHI (ICC: 0.80), the arousal index (0.76), and the % sleep time in slow-wave sleep (0.73). We have demonstrated the comparability of the apnea estimates (AHI) determined from limited channel studies obtained at in-home settings with in full in-laboratory polysomnography. In addition to our published validation study, we more recently compared the AHI in 169 Cleveland Family Study participants undergoing both assessments (in-home and in-laboratory) within one week apart. These showed excellent levels of agreement (ICC=0.83), demonstrating the feasibility of examining data from either in-home or in-laboratory studies for apnea phenotyping. Data collected in the GCRC were obtained, when possible, with comparable, if not identical techniques, as were the same measures collected at prior exams performed in the participants' homes. To address the comparability of data collected over different exams, we calculated the crude age-adjusted correlations ~3 year within individual correlations between measures made in the most recent GCRC exam with measures made in a prior exam and demonstrated excellent levels of agreement for BMI (r=.91); waist circumference (0.91); FVC (0.88); and FEV1 (0.86). As expected due to higher biological and measurement variability, 149 somewhat lower 3-year correlations were demonstrated for SBP (0.56); Diastolic BP (0.48); AHI (0.62); and nocturnal oxygen desaturation (0.60).

NHLBI Candidate-gene Association Resource. The NHLBI initiated the Candidate gene Association Resource (CARe) to create a shared genotype/phenotype resource for analyses of the association of genotypes with phenotypes relevant to the mission of the NHLBI. The resource comprises nine cohort studies funded by the NHLBI: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Cleveland Family Study (CFS), Coronary Artery Risk Development in Young Adults (CARDIA), Cooperative Study of Sickle Cell Disease (CSSCD), Framingham Heart Study (FHS), Jackson Heart Study (JHS), Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). A database of genotype and phenotype data will be created that includes records for approximately 50,000 study participants with approximately 50,000 SNPs from more than 1,200 selected candidate genes. In addition, a genome wide association study using a 1,000K SNP Chip will be conducted on approximately 9,500 African American participants drawn from the 50,000 participants in the nine cohorts.

Some relevant CARe publications
CARe Study: PMID 20400780
CVD Chip Design: PMID 18974833

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

Cases were probands with laboratory-diagnosed obstructive sleep apnea (AHI > 15 or treated with CPAP). All cases and their first degree and selective second degree relatives and spouses comprised the "case family" sample.

Control probands were selected as a neighbor of the case proband. Their first degree relatives and spouses comprised the control family sample.

Exclusion criteria: inability to provide informed consent; no family relationship with cases or controls. Additional exclusion criteria for cases were known congenital disorder associated with sleep apnea.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Targeted Region Genotyping Illumina CVDSNP55v1_A 49094 1050734
Whole Genome Genotyping Affymetrix AFFY_6.0 934940 52074
Study History

The Cleveland Family Study contains longitudinal data (multiple observations per person) sent to CARe. Exam visits occurred as many as 4 times over a 15 year time interval. Unlike some of the other CARe cohorts, new participants joined the study during subsequent waves of data collection and thus data are available from one to four exams per participant. The variable named VISIT denotes the type of visit and are labeled as VISIT #1 (1990-2001), VISIT #2 (1996-2001), VISIT #3 (1999-2001) and VISIT #5 (2001-2005) (there is no VISIT #4). These visits did not occur in "waves", instead they reflect which visit number was recorded. Recruitment was rolling, thus some individuals had a first visit (VISIT=1) after others had a second or third visit (VISIT = 2 or 3).

The first 3 visits occurred in participants' homes. Individuals who participated in visits 2 and 3 included as many participants who were available for examination from a prior visit. There were also additional family members and new minority families recruited later and recorded as visit 1 or 5, depending on type of data collected. Visit 5 occurred in a dedicated clinical research facility (GCRU). This visit targeted minority families and families in whom a prior microsatellite exam had been conducted (selected for genetic informativity). Data collection for visit 5 was more comprehensive-it generally included prior measurements made as well as more detailed biochemical data, ECGs, endothelial function, and sleep staging data. Thus, the data from VISIT = 5 accounts for the most recent visit for data collected on individuals in the Cleveland Family Study and represents the most complete data collection but only includes data for 735 participants.

Selected publications
Diseases/Traits Related to Study (MESH terms)
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Study Attribution