Search PubMed⌕ Search

Biomedical subjects

A S Whittemore

Publications and source records attributed to A S Whittemore.

At least 19 recordsLinked to original sources
PubMed2000

Detection of disease genes by use of family data. I. Likelihood-based theory.

We present a class of likelihood-based score statistics that accommodate genotypes of both unrelated individuals and families, thereby combining the advantages of case-control and family-based designs. The likelihood extends the one proposed by Schaid and colleagues (Schaid and Sommer 1993, 1994; Schaid 1996; Schaid and Li 1997) to arbitrary family structures with arbitrary patterns of missing data and to dense sets of multiple markers. The score statistic comprises two component test statistics. The first component statistic, the nonfounder statistic, evaluates disequilibrium in the transmission of marker alleles from parents to offspring. This statistic, when applied to nuclear families, generalizes the transmission/disequilibrium test to arbitrary numbers of affected and unaffected siblings, with or without typed parents. The second component statistic, the founder statistic, compares observed or inferred marker genotypes in the family founders with those of controls or those of some reference population. The founder statistic generalizes the statistics commonly used for case-control data. The strengths of the approach include both the ability to assess, by comparison of nonfounder and founder statistics, the potential bias resulting from population stratification and the ability to accommodate arbitrary family structures, thus eliminating the need for many different ad hoc tests. A limitation of the approach is the potential power loss and/or bias resulting from inappropriate assumptions on the distribution of founder genotypes. The systematic likelihood-based framework provided here should be useful in the evaluation of both the relative merits of case-control and various family-based designs and the relative merits of different tests applied to the same design. It should also be useful for genotype-disease association studies done with the use of a dense set of multiple markers.

Alleles↗
PubMed2000

Detection of disease genes by use of family data. II. Application to nuclear families.

Two likelihood-based score statistics are used to detect association between a disease and a single diallelic polymorphism, on the basis of data from arbitrary types of nuclear families. The first statistic, the nonfounder statistic, extends the transmission/disequilibrium test to accommodate affected and unaffected offspring and missing parental genotypes. The second statistic, the founder statistic, compares observed or inferred parental genotypes with those of some reference population. In this comparison, the genotypes of affected parents or of those with many affected offspring are weighted more heavily than are the genotypes of unaffected parents or of those with few affected offspring. Genotypes of single unrelated cases and controls can be included in this analysis. We illustrate the two statistics by applying them to data on a polymorphism of the SDR5A2 gene in nuclear families with multiple cases of prostate cancer. We also use simulations to compare the power of the nonfounder statistic with that of the score statistic, on the basis of the conditional logistic regression of offspring genotypes.

Alleles↗
PubMed2000

Differences in socioeconomic status and survival among white and black men with prostate cancer.

After diagnosis with prostate cancer, Black men in the United States have poorer survival than White men, even after controlling for differences in cancer stage. The extent to which these racial survival differences are due to biologic versus non-biologic factors is unclear, and it has been hypothesized that differences associated with socioeconomic status (SES) might account for much of the observed survival difference. The authors examined this hypothesis in a cohort study, using cancer registry and US Census data for White and Black men with incident prostate cancer (n = 23,334) who resided in 1,005 census tracts in the San Francisco Bay Area during 1973-1993. Separate analyses were conducted using two endpoints: death from prostate cancer and death from other causes. For each endpoint, death rate ratios (Blacks vs. Whites) were computed for men diagnosed at ages <65 years and at ages > or =65 years. These data suggest that differences associated with SES do not explain why Black men die from prostate cancer at a higher rate when compared with White men with this condition. However, among men with prostate cancer, SES-associated differences appear to explain almost all of the racial difference in risk of death from other causes.

Black or African American↗
PubMed1999

Estimating genetic influence on disease from population-based case-control data: application to cancers of the breast and ovary.

We describe genetic mixture models and goodness-of-fit statistics for evaluating the joint effects of genetic and environmental factors on the risk of chronic diseases. We focus particularly on situations wherein the gene(s) of interest play roles in several diseases, and death due to one disease can censor the occurrence of others. We use the methods to investigate the risks of cancers of the breast and ovary associated with germline mutations of BRCA1, using data pooled from three population-based U.S. case-control studies of ovarian cancer. We evaluate the goodness-of-fit of the genetic models by comparing the predicted numbers of diseased mother-daughter and sister-sister pairs to the numbers observed. We also use simulations to examine the performance of estimates obtained from such complex mixture models, and the contribution of control families to the precision of parameter estimates.

Adolescent↗
PubMed1999

Pregnancy recency and risk of ovarian cancer.

OBJECTIVE: A recent analysis suggested that ovarian cancer risk increased with time since last birth, possibly because of some aspect of pregnancy that affects the clearance of cells that have undergone malignant transformation. We analyzed data from four case-control studies pertaining to ovarian cancer risk in relation to age at first pregnancy, age at last pregnancy, and years since last pregnancy: 628 cases and 3432 neighborhood or population controls, ages 18-79, were included. METHODS: We used logistic regression to analyze associations between ovarian cancer risk, controlling for study, age (at diagnosis or corresponding reference age for controls), race, parity, oral contraceptive use, tubal ligation, family history of ovarian or breast cancer, and excluding women with a history of infertility. RESULTS: An early age at first pregnancy was associated with an increased risk of ovarian cancer (odds ratio 1.4, 95% confidence interval (1.1-1.8) for ages < or =19 compared to > or =25). Years since last pregnancy was also associated with increased ovarian cancer risk, with odds ratios of 1.4, 1.4, 1.8, and 2.1 for 10-14, 15-19, 20-24, and > or =25 years compared to 0-9 years (trend test p = 0.004), respectively. CONCLUSION: These observations support the results from the previous study, and raise additional questions about the role of pregnancy in the etiology of ovarian cancer.

Adolescent↗
PubMed1999

Power of association and linkage tests when the disease alleles are unobserved.

Genomewide association studies have been advocated as a promising alternative to genomewide linkage scans for detection of small-effect genes in complex diseases. Comparisons of power and sample size between the two strategies have shown considerable advantages for the association studies. These comparisons assume that the set of markers includes the exact disease-related polymorphism. A concern, however, is that the power of an association study decreases when this is not the case, because of discrepant allele frequencies and less-than-maximum disequilibrium between the disease-related polymorphism and its nearest marker. Here, we quantify this concern by comparing the sample sizes needed by the two strategies when the markers exclude the disease-related polymorphism. For affected sib pairs and their parents, we found that incomplete disequilibrium and differing allele frequencies can have substantial negative impact on the power of association studies, resulting, in some circumstances, in little gain and even in loss of power, compared with linkage analysis. We provide some guidelines for choosing between strategies, for the detection of genes for complex diseases.

Alleles↗
PubMed1999

Multipoint linkage analysis. A cautionary note.

Multipoint linkage analysis is commonly used to evaluate linkage of a disease to multiple markers in a small region. Multipoint analysis is particularly powerful when the IBD relations of family members at the trait locus are ambiguous. The increased power arises because, unlike single-marker analyses, multipoint analysis uses haplotype information from several markers to infer the IBD relations. We wish to temper this advantage with a cautionary note: multipoint analysis is sensitive to power loss due to misspecification of intermarker distances. Such misspecification is especially problematic when dealing with closely spaced markers. We present computer simulations comparing the power of single-point and multipoint analyses, both when IBD relations are ambiguous, and when the intermarker distances are misspecified. We conclude that when evaluating markers in a small region to confirm or refute previous findings, a situation in which p values of modest statistical significance are important, single marker analyses may provide more reliable measures of the strength of support for linkage than multipoint statistics.

Computer Simulation↗
PubMed1999

The Eighth AACR American Cancer Society Award lecture on cancer epidemiology and prevention. Genetically tailored preventive strategies: an effective plan for the twenty-first century? American Association for Cancer Research.

A preventive strategy of considerable appeal would offer specific lifestyle changes and preventive interventions to people at increased cancer risk because of inherited susceptibility. The hope for such a strategy stems in part from the variation in risk among carriers of cancer-predisposing mutations. For example, despite the high risks of cancers of the breast and ovary among BRCA1 and BRCA2 mutation carriers, some 30% of these women are estimated to reach age 70 years without developing either cancer. We need to know what protects these women, compared with carriers who do develop these malignancies. Apart from chance, possible explanations include variation in type of mutation, in genotypes at other loci, or in potentially modifiable lifestyle characteristics. This article reviews our present knowledge about risks for cancers of the colorectum, female breast, and ovary in carriers of highly penetrant germ-line mutations of susceptibility genes. The paper also reviews our present knowledge about options for reducing these risks through changes in lifestyle, chemopreventive agents, and prophylactic surgery. It concludes with a discussion of what we need to know to offer those with inherited susceptibility safe, effective options for preventing these cancers and to provide a framework for deciding among the options.

Breast Neoplasms↗
PubMed1998

Race, prostate cancer survival, and membership in a large health maintenance organization.

BACKGROUND: Population-based cancer registry data have shown that black men with prostate cancer have poorer stage-specific survival than white men, while studies in equal-access health care systems have not found racial differences in stage-specific survival. This study was designed to test the hypothesis that black men and white men with prostate cancer have equal stage-specific survival in equal-access health care systems. METHODS: We conducted a cohort study using cancer registry data from all incident cases of prostate cancer occurring in a five-county San Francisco Bay Area region. Incident cases occurred among members (5263 cases, from January 1973 through June 1995) and nonmembers (16,019 cases, from January 1973 through December 1992) of the Kaiser Permanente Medical Care Program, a large health maintenance organization. Death rate ratios (DRRs, black men versus white men) for Kaiser members and nonmembers were computed for all stages combined (adjusting for age and stage) and for each stage (adjusting for age). RESULTS: Among Kaiser members, adjusted DRRs comparing black men with white men were as follows: all stages combined, 1.28 (95% confidence interval [CI] = 1.14-1.44); local stage, 1.23 (95% CI = 1.01-1.51); regional stage, 1.30 (95% CI = 0.97-1.75); and distant stage, 1.27 (95% CI = 1.07-1.50). Corresponding DRRs for nonmembers were as follows: all stages combined, 1.22 (95% CI = 1.14-1.30); local stage, 1.24 (95% CI = 1.09-1.41); regional stage, 1.48 (95% CI = 1.29-1.68); and distant stage, 1.01 (95% CI = 0.91-1.12). CONCLUSIONS: These results show poorer prostate cancer survival for black men compared with white men in an equal-access medical care setting. The findings are most consistent with the hypothesis of increased tumor virulence in blacks.

Black or African American↗
PubMed1998

Simple, robust linkage tests for affected sibs.

Parametric-linkage analysis applied to large pedigrees with many affected individuals has helped in the identification of highly penetrant genes; but, for diseases lacking a clear Mendelian inheritance pattern or caused by several genes of low to moderate penetrance, a more robust strategy is nonparametric analysis applied to small sets of affected relatives, such as affected sib pairs. Here we show that the robustness of affected-sib-pair tests is related to the shape of the constraint set for the sibs' identity-by-descent (IBD) probabilities. We also derive a set of constraints for the IBD probabilities of affected sib triples and use common features of the shapes of the two constrain sets to introduce new nonparametric tests (called "minmax" tests) that are more robust than those in current use. Asymptotic-power computations support the robustness of the proposed minmax tests.

Automation↗
PubMed1997

Different disease rates in two populations: how much is due to differences in risk factors?

Two populations with different disease rates may differ in their risk factors for the disease. If so, it is desirable to know what proportion of the disease excess in the high-risk population is attributable to its greater exposure to the risk factors. This proportion has been called the relative attributable risk (RAR). A related measure is the adjusted relative risk (ARR), defined as the ratio of rates in high-risk to low-risk populations that would be observed if the distribution of risk factors in the high-risk population equalled that of the low-risk population. We present methods for obtaining consistent estimates and asymptotic confidence intervals for both the RAR and the ARR using data from case-control studies in the two populations. The methods are applied to the problem of estimating the differences in ovarian cancer incidence between U.S. white women (high-risk) and U.S. black women (low-risk) attributable to differences in reproductive risk factors. Simulations show that the methods perform well; however, when the true RAR is close to 0 or 1 or when sample sizes are small, RAR estimates may fall outside the unit interval. We discuss circumstances when the true RAR lies outside the unit interval; in such circumstances the ARR is easier to interpret.

Black or African American↗
PubMed1997

Serum levels of prostate-specific antigen among Japanese-American and native Japanese men.

BACKGROUND: Fourfold to sixfold higher prostate cancer rates in Japanese-American men in the United States compared with Japanese men in Japan have been cited to support a role for environmental risk factors in the etiology of the disease. To examine the hypothesis that part or all of the elevated prostate cancer rates in Japanese-American men may reflect more intensive prostate cancer screening in the United States than in Japan, we compared prostate-specific antigen (PSA) levels in community-based samples of serum from men without prostate cancer. METHODS: Japanese-American men aged 40-85 years and native Japanese men aged 40-89 years with no history of prostate cancer provided sera, respectively, in the United States from March 1990 through March 1992 (n = 237) or in Japan from January 1992 through December 1993 (n = 3522). Age-specific PSA levels were used to estimate the prevalences of undetected prostate cancer in the two populations. RESULTS: Age-specific mean PSA levels were significantly lower in Japanese-Americans than in native Japanese (two-sided P<.001). The prevalence of an elevated PSA level increased with age in both populations and exceeded 5% among men aged 60 years or more. Combined with data on prevalence of detected prostate cancer in the two populations, our data suggest that some 10.0% of Japanese-Americans aged 75 years have prostate cancer, with 31% of that fraction remaining undiagnosed. The corresponding estimates in Japan are a total cancer prevalence of 5.4%, of which 81% has not been detected clinically. CONCLUSIONS: The total cancer prevalence ratio 10.0/5.4 = 1.9 (95% confidence interval = 1.5-2.3) in Japanese-American men compared with Japanese men in Japan suggests an increased risk for Japanese-American men, but of less magnitude than the fourfold to sixfold increase indicated by the incidence data.

Adult↗