Biomedical subjects

S Ripatti

Publications and source records attributed to S Ripatti.

8 recordsLinked to original sources

PubMed2001

Joint modeling of genetic association and population stratification using latent class models.

We show how latent class log-linear models can be used to test for an association between a candidate gene and a disease phenotype in a stratified population when the stratification is unobserved. The stratification may arise because of several ethnic groups or immigration and may lead to spurious associations between several loci and the disease. The information about the stratification is drawn from additional markers that are chosen to be independent of the disease and unlinked to the candidate gene and to each other within each population stratum. We use the EM algorithm to simultaneously estimate all the model parameters, including proportions of individuals in the latent population strata. The latent class model is used to test the phenotype association of single nucleotide polymorphism markers in four candidate regions in population-based case-control data selected from simulated Genetic Analysis Workshop (GAW) 12 population isolate 30. The analysis clearly demonstrates how the number of false positive associations can be reduced when the model accounts for population stratification.

Case-Control Studies↗

PubMed2001

Bayesian association mapping for quantitative traits in a mixture of two populations.

We introduce a novel Bayesian approach to estimate and account for population structure simultaneously with association mapping of multiple quantitative trait loci. The method is designed for an analysis of unrelated individuals from a mixture of two populations (no admixture), where the individual population memberships are unknown. In our approach, the population structure is estimated and accounted for by using data on additional "grouping" markers which are assumed to be in Hardy-Weinberg equilibrium within the populations but have different allele frequencies between the populations. We use Bayesian hierarchical modeling and Markov chain Monte Carlo estimation, where we allow both population stratification and genetic heterogeneity. In our model the number of quantitative trait loci and their positions are treated as random variables, and we obtain their posterior distributions. Here we select the candidate and the grouping markers based on results from a preliminary SOLAR analysis.

Bayes Theorem↗

PubMed2001

Educational differences in lung cancer mortality in male smokers.

BACKGROUND: To assess the extent of lung cancer mortality differentials by education while adjusting for exposure to tobacco smoke and asbestos based on survey questions. METHODS: Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study of 50-69-year-old Finnish male smokers enrolled 1985-1988. These analyses are based on the placebo group and the alpha-tocopherol supplementation group, altogether 14 011 men, with full information on tobacco smoking. Mortality follow-up was to the end of April 1993 and it was based on the complete death certificate register of the Statistics Finland. RESULTS: Lung cancer mortality of basic-educated men was 32% (rate ratio [RR] = 1.32; 95% CI : 0.93-1.87) higher than that of better-educated men in the ATBC Study. The excess is practically unchanged when additional adjustment was made for age at initiation, duration of smoking, current smoking at baseline and at first follow-up, smoke inhalation, occupational exposure to asbestos and interactions between asbestos exposure and all smoking variables. This excess mortality was about 40% of the similar excess observed in the general population of men of similar age. CONCLUSIONS: Educational differences in lung cancer mortality in the total Finnish population are likely to be mainly caused by differences in exposure, particularly to active smoking. Further understanding of the determinants and consequences of socioeconomic differences in smoking behaviour are of major scientific and public health importance.

Aged↗

PubMed2000

Estimation of multivariate frailty models using penalized partial likelihood.

There exists a growing literature on the estimation of gamma distributed multiplicative shared frailty models. There is, however, often a need to model more complicated frailty structures, but attempts to extend gamma frailties run into complications. Motivated by hip replacement data with a more complicated dependence structure, we propose a model based on multiplicative frailties with a multivariate log-normal joint distribution. We give a justification and an estimation procedure for this generally structured frailty model, which is a generalization of the one presented by McGilchrist (1993, Biometrics 49, 221-225). The estimation is based on Laplace approximation of the likelihood function. This leads to estimating equations based on a penalized fixed effects partial likelihood, where the marginal distribution of the frailty terms determines the penalty term. The tuning parameters of the penalty function, i.e., the frailty variances, are estimated by maximizing an approximate profile likelihood. The performance of the approximation is evaluated by simulation, and the frailty model is fitted to the hip replacement data.

Biometry↗

PubMed1998

Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease.

BACKGROUND: Oxidized low-density lipoprotein is involved in the pathogenesis of atherosclerosis. In epidemiological studies antioxidants have been inversely related with coronary heart disease. Findings from controlled trials are inconclusive. METHODS: We studied the primary preventive effect of vitamin E (alpha tocopherol) and beta carotene supplementation on major coronary events in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a controlled trial undertaken primarily to examine the effects of these agents on cancer. A total of 27 271 Finnish male smokers aged 50 to 69 years with no history of myocardial infarction were randomly assigned to receive vitamin E (50 mg), beta carotene (20 mg), both agents, or placebo daily for 5 to 8 years (median, 6.1 years). The end point was the first major coronary event, either nonfatal myocardial infarction (surviving at least 28 days; n = 1204) or fatal coronary heart disease (n = 907). RESULTS: The incidence of primary major coronary events decreased 4% (95% confidence interval, -12% to 4%) among recipients of vitamin E and increased 1% (95% confidence interval, -7% to 10%) among recipients of beta carotene compared with the respective nonrecipients. Neither agent affected the incidence of nonfatal myocardial infarction. Supplementation with vitamin E decreased the incidence of fatal coronary heart disease by 8% (95% confidence interval, -19% to 5%), but beta carotene had no effect on this end point. CONCLUSIONS: Supplementation with a small dose of vitamin E has only marginal effect on the incidence of fatal coronary heart disease in male smokers with no history of myocardial infarction, but no influence on nonfatal myocardial infarction. Supplementation with beta carotene has no primary preventive effect on major coronary events.

Aged↗

PubMed1998

Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial.

BACKGROUND: Epidemiologic studies have suggested that vitamin E and beta-carotene may each influence the development of prostate cancer. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a controlled trial, we studied the effect of alpha-tocopherol (a form of vitamin E) and beta-carotene supplementation, separately or together, on prostate cancer in male smokers. METHODS: A total of 29133 male smokers aged 50-69 years from southwestern Finland were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or placebo daily for 5-8 years (median, 6.1 years). The supplementation effects were estimated by a proportional hazards model, and two-sided P values were calculated. RESULTS: We found 246 new cases of and 62 deaths from prostate cancer during the follow-up period. A 32% decrease (95% confidence interval [CI] = -47% to -12%) in the incidence of prostate cancer was observed among the subjects receiving alpha-tocopherol (n = 14564) compared with those not receiving it (n = 14569). The reduction was evident in clinical prostate cancer but not in latent cancer. Mortality from prostate cancer was 41% lower (95% CI = -65% to -1%) among men receiving alpha-tocopherol. Among subjects receiving beta-carotene (n = 14560), prostate cancer incidence was 23% higher (95% CI = -4%-59%) and mortality was 15% higher (95% CI = -30%-89%) compared with those not receiving it (n = 14573). Neither agent had any effect on the time interval between diagnosis and death. CONCLUSIONS: Long-term supplementation with alpha-tocopherol substantially reduced prostate cancer incidence and mortality in male smokers. Other controlled trials are required to confirm the findings.

Anticarcinogenic Agents↗

PubMed1998

Effects of alpha tocopherol and beta carotene supplements on symptoms, progression, and prognosis of angina pectoris.

OBJECTIVE: To evaluate the effects of alpha tocopherol and beta carotene supplements on recurrence and progression of angina symptoms, and incidence of major coronary events in men with angina pectoris. DESIGN: Placebo controlled clinical trial. SETTING: The Finnish alpha tocopherol beta carotene cancer prevention study primarily undertaken to examine the effects of alpha tocopherol and beta carotene on cancer. SUBJECTS: Male smokers aged 50-69 years who had angina pectoris in the Rose chest pain questionnaire at baseline (n = 1795). INTERVENTIONS: alpha tocopherol (vitamin E) 50 mg/day, beta carotene 20 mg/day or both, or placebo in 2 x 2 factorial design. MAIN OUTCOME MEASURES: Recurrence of angina pectoris at annual follow up visits when the questionnaire was readministered; progression from mild to severe angina; incidence of major coronary events (non-fatal myocardial infarction and fatal coronary heart disease). RESULTS: There were 2513 recurrences of angina pectoris during follow up (median 4 years). Compared to placebo, the odds ratios for recurrence in the active treatment groups were: alpha tocopherol only 1.06 (95% confidence interval (CI) 0.85 to 1.33), alpha tocopherol and beta carotene 1.02 (0.82 to 1.27), beta carotene only 1.06 (0.84 to 1.33). There were no significant differences in progression to severe angina among the groups given supplements or placebo. Altogether 314 major coronary events were observed during follow up (median 5.5 years) and the risk for them did not differ significantly among the groups given supplements or placebo. CONCLUSIONS: There was no evidence of beneficial effects for alpha tocopherol or beta carotene supplements in male smokers with angina pectoris, indicating no basis for therapeutic or preventive use of these agents in such patients.

Aged↗

PubMed1997

Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction.

BACKGROUND: Epidemiological data suggest that the intake of antioxidants such as alpha-tocopherol (vitamin E) and beta-carotene has an inverse correlation with the incidence of coronary heart disease. The results from clinical trials of antioxidant supplementation in people with known coronary heart disease are inconclusive. METHODS: We studied the frequency of major coronary events in 1862 men enrolled in the alpha-tocopherol beta-carotene Cancer Prevention Study (smokers aged between 50 and 69 years) who had a previous myocardial infarction. In this randomised, double-blind. placebo-controlled study, men had received dietary supplements of alpha-tocopherol (50 mg/day), beta-carotene (20 mg/day), both, or placebo. The median follow-up was 5.3 years. The endpoint of this substudy was the first major coronary event after randomisation. Analyses were by intention to treat. FINDINGS: 424 major coronary events (non-fatal myocardial infarction and fatal coronary heart disease) occurred during follow-up. There were no significant differences in the number of major coronary events between any supplementation group and the placebo group (alpha-tocopherol 94/466; beta-carotene 113/461; alpha-tocopherol and beta-carotene 123/497; placebo 94/438 [log-rank test, p = 0.25]). There were significantly more deaths from fatal coronary heart disease in the beta-carotene (74/461, multivariate-adjusted relative risk 1.75 [95% CI 1.16-2.64], p = 0.007) and combined alpha-tocopherol and beta-carotene groups (67/497, relative risk 1.58 [1.05-2.40], p = 0.03) than in the placebo group (39/438), but there was no significant increase in the alpha-tocopherol supplementation group (54/466, relative risk 1.33 [0.86-2.05], p = 0.20). INTERPRETATION: The proportion of major coronary events in men with a previous myocardial infarction who smoke was not decreased with either alpha-tocopherol or beta-carotene supplements. In fact, the risk of fatal coronary heart disease increased in the groups that received either beta-carotene or the combination of alpha-tocopherol and beta-carotene; there was a non-significant trend of increased deaths in the alpha-tocopherol group. We do not recommend the use of alpha-tocopherol or beta-carotene supplements in this group of patients.

Aged↗