Population-based Case-cohort Study Research Articles

Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a population-based prospective cohort study (MONICA/KORA).

Early repolarization pattern (ERP) on electrocardiogram was associated with idiopathic ventricular fibrillation and sudden cardiac arrest in a case-control study and with cardiovascular mortality in a Finnish community-based sample. We sought to determine ERP prevalence and its association with cardiac and all-cause mortality in a large, prospective, population-based case-cohort study (Monitoring of Cardiovascular Diseases and Conditions [MONICA]/KORA [Cooperative Health Research in the Region of Augsburg]) comprised of individuals of Central-European descent. Electrocardiograms of 1,945 participants aged 35-74 y, representing a source population of 6,213 individuals, were analyzed applying a case-cohort design. Mean follow-up was 18.9 y. Cause of death was ascertained by the 9th revision of the International Classification of Disease (ICD-9) codes as documented in death certificates. ERP-attributable effects on mortality were determined by a weighted Cox proportional hazard model adjusted for covariables. Prevalence of ERP was 13.1% in our study. ERP was associated with cardiac and all-cause mortality, most pronounced in those of younger age and male sex; a clear ERP-age interaction was detected (p = 0.005). Age-stratified analyses showed hazard ratios (HRs) for cardiac mortality of 1.96 (95% confidence interval [CI] 1.05-3.68, p = 0.035) for both sexes and 2.65 (95% CI 1.21-5.83, p = 0.015) for men between 35-54 y. An inferior localization of ERP further increased ERP-attributable cardiac mortality to HRs of 3.15 (95% CI 1.58-6.28, p = 0.001) for both sexes and to 4.27 (95% CI 1.90-9.61, p<0.001) for men between 35-54 y. HRs for all-cause mortality were weaker but reached significance. We found a high prevalence of ERP in our population-based cohort of middle-aged individuals. ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 y. An inferior localization of ERP was associated with a particularly increased risk. Please see later in the article for the Editors' Summary.

Leptin, adiponectin, their ratio and risk of coronary heart disease: Results from the MONICA/KORA Augsburg Study 1984–2002

ObjectiveDespite modulating a number of metabolic processes linked to atherosclerosis, including glucose regulation, hematopoiesis, fatty acid catabolism and angiogenesis, the potential association of adiponectin and leptin with coronary heart disease is still a matter of controversy. MethodsWe conducted a population-based case-cohort study within the MONICA/KORA Augsburg studies. Serum levels of adipokines were measured in 333 case subjects with incident CHD and 1,728 non-case subjects selected from a source population of 9300 middle-aged men and women. Mean follow-up was 10.8±4.6 years. We sought to analyze the association of leptin and adiponectin and their ratio with CHD. ResultsAfter adjustment for various confounding factors the hazard ratios and 95% confidence intervals comparing tertile extremes were 0.79 (0.53–1.17) for leptin (top vs bottom tertile) and 0.87 (0. 62–1.23) for adiponectin (bottom vs top tertile), respectively. Furthermore, the ratio of leptin/adiponectin also showed no association with CHD (HR 1.01 (0.68–1.51)). ConclusionsThe present study reports the association of leptin and adiponectin with incident CHD in a large population-based cohort. In contrast to fairly strong associations previously reported, our findings indicate no clinically relevant association between leptin, adiponectin and their ratio with the risk of CHD after adjustment for potential confounders.

Genetic variants in the USF1 gene are associated with low-density lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002

Upstream transcription factor 1 (USF1) regulates genes of glucose and lipid metabolism. Polymorphisms in the USF1 gene showed association with familial combined hyperlipidemia and lipid parameters. The aim of our study was to examine the associations between USF1 polymorphisms and lipid parameters as well as incident type 2 diabetes mellitus (T2DM) in German Caucasians. We genotyped eight polymorphisms in the USF1 gene in 2067 middle-aged (35-74 years) individuals including 498 incident T2DM cases and 1569 non-cases of the population-based case-cohort study from the MONICA/KORA Augsburg project. Six polymorphisms and their haplotypes were analyzed using multivariable linear regression and Cox proportional hazards models. Polymorphism rs3737787 was inversely associated with incident T2DM in women with decreased risk for female heterozygotes compared with women homozygous for the major allele (Hazard ratio=0.57; 95% confidence intervals: 0.38-0.87; P=0.008). After correction for multiple testing, significance remained. Polymorphisms rs3813609 and rs1556259 were significantly associated with reduction in low-density lipoprotein (LDL) cholesterol (p(NOM)=0.001; p(NOM)=0.00002) in women. Analyses also indicated associations of haplotypes with LDL cholesterol in women, but the association lost statistical significance after correction for multiple testing. Total serum cholesterol (TC) and high-density lipoprotein (HDL) cholesterol were weakly associated (P<0.05) with USF1 polymorphisms in women. No significant associations were found in men. In this large population-based study, statistically significant associations of USF1 polymorphisms with incident T2DM and LDL cholesterol were found in women, but not in men. Genetic variants in the USF1 gene showed weak or no associations with TC and HDL cholesterol.

Perinatal characteristics and risk of neuroblastoma

Neuroblastoma (NB), a tumor of the sympathetic nervous system, is the most common infant malignancy. The etiology of NB is largely unknown. We explored the association between birth record variables and subsequent NB development in a population-based case-cohort study in Minnesota by linking the birth and cancer registries. NB cases included 155 children born during 1976-2004 who were diagnosed from 28 days through 14 years of age. The comparison group included 8,752 individuals randomly sampled from the birth cohort of cases. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Controlling for birth year and sex, maternal history of one fetal loss (HR = 1.7, 95% CI 1.2-2.5), maternal prenatal drug-use (recorded starting in 1992) (HR = 5.7, 95% CI 2.3-14) and child's small size for gestational age (HR = 2.1, 95% CI 1.1-4.0) were significantly associated with NB. Age group specific analyses indicated that maternal hypertension (HR = 3.0, 95% CI 1.3-7.2) and maternal age <20 years (HR = 2.6, 95% CI 1.1-6.1) increased risks for infant NB only. Our study provides evidence that a few perinatal exposures as recorded in birth records may play a role in NB etiology.

A Population-based Case-cohort Study of the Risk of Myocardial Infarction Following Radiation Therapy for Breast Cancer

A Population-based Case-cohort Study of the Risk of Myocardial Infarction Following Radiation Therapy for Breast Cancer

A population-based case-cohort study of the risk of myocardial infarction following radiation therapy for breast cancer

Objective To describe the risk of acute myocardial infarction (AMI) after radiation therapy (RT) for breast cancer (BrCa) in an exposed population. Methods We identified and validated cases of AMI (vAMI), by electrocardiographic or enzyme criteria, among all 6680 women who received post-operative RT following lumpectomy or mastectomy, within 12 months following diagnosis of BrCa between 1982 and 1988 in Ontario, Canada. We identified women without vAMI whose death certification was ascribed to AMI (dAMI). We abstracted risk factors and treatment exposures for a random sample of women from the 6680, and for all with vAMI or dAMI. The hazards of vAMI and of dAMI were estimated using multivariate Cox proportional hazards models, corrected for study design. Results We validated 121 cases of vAMI and identified 92 cases of dAMI. The risk of vAMI associated with RT to the left breast HR = 1.96 (1.09, 3.54) among women at age ⩾ 60 at time of RT, adjusted for history of smoking and prior MI. The adjusted HR dAMI = 1.90 (1.08, 3.35) for exposure to anterior internal mammary node (IMC) RT. Among women who received anterior left breast boost RT, increasing area of the boost is associated with adjusted HR vAMI = 1.02 (1.00, 1.03)/cm 2, and adjusted HR dAMI = 1.02 (1.01, 1.03)/cm 2. Conclusion The risks of vAMI and dAMI following RT for BrCa are related to anatomic sites of RT (left breast, area of anterior left breast boost field, and anterior IMC field).

Widening social inequalities in risk for sudden infant death syndrome.

In 1994, the US Public Health Service launched the "Back to Sleep" campaign, promoting the supine sleep position to prevent sudden infant death syndrome (SIDS). Studies of SIDS in the United States have generally found socioeconomic and race disparities. Our objective was to see whether the "Back to Sleep" campaign, which involves an effective, easy, and free intervention, has reduced social class inequalities in SIDS. We conducted a population-based case-cohort study during 2 periods, 1989 to 1991 and 1996 to 1998, using the US Linked Birth/Infant Death Data Sets. Case group was infants who died of SIDS in infancy (N = 21 126); control group was a 10% random sample of infants who lived through the first year and all infants who died of other causes (N=2241218). Social class was measured by mother's education level. There was no evidence that inequalities in SIDS were reduced after the Back to Sleep campaign. In fact, odds ratios for SIDS associated with lower social class increased between 1989-1991 and 1996-1998. The race disparity in SIDS increased after the Back to Sleep campaign. The introduction of an inexpensive, easy, public health intervention has not reduced social inequalities in SIDS; in fact, the gap has widened. Although the risk of SIDS has been reduced for all social class groups, women who are more educated have experienced the greatest decline.

A genetic polymorphism in prostaglandin synthase 2 (8473, T→C) and the risk of lung cancer

Prostaglandin synthase 2 (PTGS2) mediated production of prostaglandins is an important step in the inflammatory response. In a population-based case-cohort study, we investigated the relationship between lung cancer and a polymorphism in PTGS2 at site 8473. Among 54,220 cohort members, 265 lung cancer cases and a comparison group of 272 individuals were identified. We found no overall significant association between the PTGS2 polymorphism and lung cancer risk, though the results indicated a lower risk in subjects carrying one copy (RR 0.87; 95% CI 0.61–1.25) or two copies (RR 0.58; 95% CI 0.30–1.12) of the variant allele compared with subjects carrying two copies of the wildtype allele. This tendency seemed to be strongest among the youngest subjects (50–55 years) with a RR on 0.48 (0.19–1.22) in carriers of one variant allele and 0.21 (0.04–1.07) in carriers of two variant alleles, and a significant trend ( P=0.04). These results indicate that PTGS2 could be implicated in the development of lung cancer.

A Population-based Case-Cohort Study to Evaluate Prehospital and Emergency Department Utilization by Homeless Patients

A Population-based Case-Cohort Study to Evaluate Prehospital and Emergency Department Utilization by Homeless Patients

Genetic polymorphisms in CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer

In a population-based case-cohort study, we have investigated the occurrence of lung cancer in relation to polymorphisms in the phase I gene cytochrome P450 1B1 and in the phase II genes glutathione S-transferase A1, NAD(P)H quinone oxidoreductase and N-acetyltransferase 2 ( NAT2). Among 54,220 cohort members, 265 lung cancer cases were identified and a sub-cohort comprising 272 individuals was used for comparison. No overall associations were found between the polymorphisms and risk of lung cancer. The NAT2 fast acetylator genotype seemed to be protective against lung cancer in light smokers (≤20 cigarettes/day) and not among heavy smokers (>20 cigarettes/day).

Glutathione S-transferase T1 null-genotype is associated with an increased risk of lung cancer.

Glutathione S-transferases (GSTs) are involved in detoxification of carcinogens, e.g., from tobacco smoke. Therefore, polymorphisms in the GST genes have been considered as potential modifiers of individual cancer risk. In a population-based case-cohort study where cases and the subcohort sample were matched on duration of smoking, we investigated the occurrence of lung cancer and histological subtypes of lung cancer in relation to deletion polymorphism in both GSTM1 and GSTT1, single nucleotide polymorphisms (SNPs) in GSTP1 (Ile105Val and Ala114Val) and a 3 base pair deletion polymorphism in GSTM3. We further investigated the effects of the GST polymorphisms on lung cancer risk within subgroups of subjects defined by gender and age. The results showed a 2.4-fold (CI = 1.31-4.41) increased risk of lung cancer in GSTT1 null-genotype carriers but no significant effects of the polymorphisms in GSTM1, GSTM3, GSTP1-105 or GSTP1-114. The association was strongest in lower age groups, with a 9.6-fold increase in risk for subjects with the GSTT1 null-genotype in the 50-55 years age interval (CI = 3.03-30.59). Positive associations were found for GSTT1 within all major histological subtypes. Squamous cell carcinoma was the histological type most strongly associated with the GSTT1 genotype, with a 5.0-fold (CI = 2.26-11.18) increase in risk for subjects carrying the GSTT1 null-genotype. The effects of the GSTT1 null-genotype seemed stronger in the presence of the GSTM1 null-genotype or the GSTP1-105 variant allele. These results suggest that the GSTT1 null-genotype is associated with an increased risk of lung cancer, especially in younger individuals.

Shoulder pain in people with a stroke: a population-based study.

To measure the occurrence of shoulder pain after stroke. To identify the factors that predict risk of shoulder pain after stroke. Auckland Stroke Study, population-based case-cohort study. All cases of stroke, including those managed outside hospital, over a 12-month period ending February 1992 were considered in Auckland. Self-reported shoulder pain at one week, one month and six months after the onset of stroke for each person. A total of 1,761 stroke events were identified. Self-reported shoulder pain among survivors increased from 256/1474 (17%) at one week, to 261/1,336 (20%) at one month and 284/1,201 (23%) at six months. Shoulder pain was positively associated with motor deficit, side of deficit and severity of deficit. In those surviving to six months after stroke, the risk of shoulder pain was higher in those with severe upper limb motor deficit (odds ratio (OR) 4.94; 95% confidence interval (CI) 3.06-7.98) and in diabetics (OR 1.57, 95% CI 1.15-2.14). Risk of shoulder pain increased with time and was lower for those in institutional care. Shoulder pain after stroke is common, especially in patients with severe sensorimotor deficits, diabetics and those living at home. Appropriate management may reduce the rate of occurrence.

Particulate matter and heart rate variability among elderly retirees: the Baltimore 1998 PM study.

This study investigates the relationship between ambient fine particle pollution and impaired cardiac autonomic control in the elderly. Heart rate variability (HRV) among 56 elderly (mean age 82) nonsmoking residents of a retirement center in Baltimore County, Maryland, was monitored for 4 weeks, from July 27 through August 22, 1998. The weather was seasonally mild (63-84 degrees F mean daily temperature) with low to moderate levels of fine particles (PM2.5 < 50 micrograms/m3). Two groups of approximately 30 subjects were examined on alternate days. A spline mixed-effects model revealed a negative relationship between outdoor 24-h average fine particulate matter (PM2.5) and high-frequency (HF) HRV that was consistent with our earlier Baltimore study for all but 2 days. These 2 days were the only days with significant precipitation in combination with elevated PM2.5. They were also unusual in that back-trajectory of their air masses was distinctly different from those on the other study days, emanating from the direction of rural Pennsylvania. Mixed-effects analysis for all 24 study days showed a small negative association of outdoor PM2.5 with HF HRV (-0.03 change in log[HF HRV] for a 10 micrograms/m3 increment in PM2.5) after adjustment for age, sex, cardiovascular status, trend, maximum temperature, average dew point temperature, random subject intercepts, and autocorrelated residuals. After excluding study days 4 and 5, this association was strengthened (-0.07 change in log[HF HRV] for 10 micrograms/m3 PM2.5, 95% CI -0.13 to -0.02) and was similar to that obtained in an earlier study (-0.12 change in log[HF HRV] for a 10 micrograms/m3 increment in outdoor PM2.5, 95% CI -0.24 to -0.00) [Liao D., Cai J., Rosamond W.D., Barnes R.W., Hutchinson R.G., Whitsel E.A., Rautaharju P., and Heiss G. Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study. The ARIC Study. Atherosclerosis Risk in Communities Study. Am J Epidemiol 1997: 145 (8): 696-706]. Acute (1 to 4 h) previous PM2.5 exposure did not have a stronger impact than the 24-h measure. A distributed lag model incorporating the six preceding 4-h means also did not indicate any effect greater than that observed in the 24-h measure. This study is consistent with earlier findings that exposures to PM2.5 are associated with decreased HRV in the elderly.

A population-based case-cohort study of drug-associated agranulocytosis.

Agranulocytosis is a life-threatening disorder, often caused by drugs. Incidences or risks of drug-induced agranulocytosis are not well known, since it is rare. To determine the risk of drug-associated agranulocytosis as a reason for admission to Dutch hospitals, we performed a population-based case-cohort study. Hospital discharge data came from the Dutch Centre for Health Care Information, Utrecht, which contains data on all general and university hospitals in the Netherlands. The reference cohort consisted of all persons in the catchment area of the Pharmaco Morbidity Record Linkage System (PHARMO RLS) in the Netherlands, composing a population of approximately 220 000 to 484 000 persons from 1987 through 1990. All admissions during that period with agranulocytosis or related diagnoses were included in the study (n = 923). The potential causes of agranulocytosis were assessed in all cases classified as probable or possible agranulocytosis. Discharge summaries were received of 753 admissions, of which 678 contained enough information for analysis. Of the 678,108 were classified as "agranulocytosis probable" or as "agranulocytosis possible." In 75 of these 108 cases, agranulocytosis had been the reason for admission. Fifteen patients had used methimazole within 10 days before developing agranulocytosis; 2, carbimazole; 9, sulfasalazine; 8, sulfamethoxazole-trimethoprim; 4, clomipramine hydrochloride; and 2, dipyrone with analgesics, yielding adjusted relative risks of agranulocytosis of 114.8 (for thyroid inhibitors combined) (95% confidence interval [CI], 60.5-218.6), 74.6 (95% CI, 36.3-167.8), 25.1 (95% CI, 11.2-55.0),20.0 (95% CI, 6.1-57.6), and 26.4 (95% CI, 4.4-11.1), respectively. The highest relative risks were found for thyroid inhibitors, sulfamethoxazole-trimethoprim, sulfasalazine, clomipramine, and dipyrone combined with analgesics.