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N Risch

Publications and source records attributed to N Risch.

At least 19 recordsLinked to original sources
PubMed1992

Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer.

This study examined risk factors for development of a contralateral breast cancer among 4,660 US women diagnosed with a first primary breast cancer between 1980 and 1982. The authors believe it to be the first prospective cohort study on this topic that has employed direct patient interviews. All subjects were interviewed within 6 months of the diagnosis of their initial tumor as part of the multi-center, population-based, case-control Cancer and Steroid Hormone Study, and they were followed until the end of 1986 through the Surveillance, Epidemiology, and End Results program. Exclusive of those diagnosed during the initial 6 months after diagnosis of a first primary, 136 second primary breast cancers were identified. Proportional hazards models were used to assess the independent effects of multiple predictors. Specific risk factors evaluated included: age at diagnosis of first primary, exposure to exogenous hormones, menstrual and reproductive histories, tumor characteristics, demographic variables, and treatment modalities. The age-specific incidence rates of second primary breast cancer were higher in all age categories than are the incidence rates of breast cancer in the general population, yet the age at diagnosis of first primary breast cancer was not an important predictor of contralateral breast cancer. The risk of contralateral breast cancer was increased among cohort members who reported a personal history of benign breast biopsy (multivariable-adjusted rate ratio (RR) = 1.69, 95% confidence interval (CI) 1.13-2.53) and in those with an initial tumor that was classified as lobular carcinoma (multivariable-adjusted RR = 1.96, 95% CI 1.17-3.27). Treatment with chemotherapy for the first primary was associated with a lower risk of development of a second breast cancer (multivariable-adjusted RR = 0.56, 95% CI 0.33-0.96), while radiation therapy had little effect on the risk (multivariable-adjusted RR = 1.19, 95% CI 0.78-1.80).

Adult↗
PubMed1992

The genetic epidemiology of second primary breast cancer.

It is well established that women with a family history of breast cancer run a higher risk of breast cancer than do women without a family history. The evidence, however, is less clear regarding a possible association between a family history of breast cancer and risk of second primaries. The purpose of this prospective study was to estimate the risk for second primary breast cancer associated with having a family history of breast, endometrial, and ovarian cancers. A cohort of 4,660 women with a first primary breast cancer diagnosed between 1980 and 1982 were interviewed as part of the Cancer and Steroid Hormone Study, a multi-center population-based case-control study, and followed through eight Surveillance, Epidemiology, and End Results (SEER) program registries for 4 to 6 years. Of these women, 136 developed a second primary breast cancer in the contralateral breast at least 6 months after diagnosis of the first primary. Cox proportional hazards modeling techniques were used to model the time to onset of second primary breast cancer while adjusting for multiple predictors. The risk of contralateral breast cancer was elevated among cohort members who reported a history of breast cancer in a first-degree relative (multivariable-adjusted rate ratio (RR) = 1.91, 95% confidence interval (CI) = 1.22-2.99). Early age at onset (< 46 years) in the relative further increased the risk of developing contralateral breast cancer (sister: multivariable-adjusted RR = 3.36, 95% CI 1.62-6.98; mother: multivariable-adjusted RR = 2.35, 95% CI 1.02-5.43). Bilateral breast cancer in mothers was also associated with more than a two and a half-fold increase in risk (multivariable-adjusted RR = 2.55, 95% CI 1.02-6.35). The association between family history of breast cancer and risk of contralateral breast cancer did not vary substantially according to age at onset of the first primary breast cancer. The age-adjusted rate ratio for development of a second primary breast cancer among women with a first-degree relative with endometrial cancer was 2.13 (95% CI 1.04-4.35), while the corresponding rate ratio among women with a family history of ovarian cancer was 1.69 (95% CI 0.42-6.83). There was little evidence that age at onset among the relatives with endometrial or ovarian cancer affected the risk. Some of these findings have not been previously reported and need replication in future studies.

Adult↗
PubMed1992

Model misspecification and multipoint linkage analysis.

Pairwise linkage analysis is robust to genetic model misspecification provided dominance is correctly specified, the primary effect being inflation of the recombination fraction. By contrast, we show that multipoint analysis under misspecified models is not robust when a putative disease locus is placed between close flanking markers, with potentially spuriously negative multipoint lod scores being produced. The problem is due to incorrect attribution of segregation of a disease allele and the consequent conclusion of (unlikely) double crossovers between flanking markers. As a possible solution, we propose the use of high disease allele frequencies, as this allows probabilistically for nonsegregation (through parental homozygosity or dual matings). We show analytically and through analysis of pedigree data simulated under a two-locus heterogeneity model that using a disease allele frequency of 0.05 in the dominant case and 0.25 in the recessive case is quite robust in producing positive multipoint lod scores with close flanking markers across a broad range of conditions including varying allele frequencies, epistasis, genetic heterogeneity and phenocopies.

Animals↗
PubMed1992

Influence of dietary fat, apolipoprotein E phenotype, and sex on plasma lipoprotein levels.

BACKGROUND: The "Western" diet, sex, and apolipoprotein (Apo) E polymorphism have been implicated as codeterminants of lipid levels. METHODS AND RESULTS: In a retrospective analysis, we evaluated the combined impact of dietary fat, sex, and Apo E phenotype on lipoprotein levels in 67 subjects fed two contrasting, metabolically controlled diets: one a "Western" diet, with a low polyunsaturated to saturated (P:S) fatty acid ratio and the other a "therapeutic" diet, with a high P:S ratio. The high P:S diet compared with P:S diet exerted a far stronger predictive influence on lipoprotein concentrations than Apo E phenotype, sex, or the latter two factors combined. Apo E phenotype alone was associated with a stepwise increase in low density lipoprotein cholesterol (LDL-C), such that 3/2 less than 3/3 less than 4/3 on either the low or the high P:S diets. On the low P:S diet only, sex was shown to be a significant predictor of high density lipoprotein cholesterol (HDL-C) levels, with women greater than men, and the associated LDL/HDL ratio with men greater than women. On the high P:S diet, women displayed a dramatic fall in HDL-C, effectively raising the LDL/HDL ratio to equivalency with men and obliterating the sex influence seen with the low P:S diet. Controlled for dietary fat, Apo E and sex exerted independent, additive effects on lipoprotein levels on the low P:S diet only. Only the Apo E phenotype remained predictive on the high P:S diet. CONCLUSIONS: Women of the Apo E 3/2 phenotype stand to benefit the least from a high P:S diet because of reduction in the more "protective" HDL-C, whereas men of the 4/3 phenotype showed the greatest improvement in the LDL/HDL ratio.

Adult↗
PubMed1992

Strong allelic association between the torsion dystonia gene (DYT1) andloci on chromosome 9q34 in Ashkenazi Jews.

The DYT1 gene responsible for early-onset, idiopathic torsion dystonia (ITD) in the Ashkenazi Jewish population, as well as in one large non-Jewish family, has been mapped to chromosome 9q32-34. Using (GT)n and RFLP markers in this region, we have identified obligate recombination events in some of these Jewish families, which further delineate the area containing the DYT1 gene to a 6-cM region bounded by loci AK1 and ASS. In 52 unrelated, affected Ashkenazi Jewish individuals, we have found highly significant linkage disequilibrium between a particular extended haplotype at the ABL-ASS loci and the DYT1 gene. The 4/A12 haplotype for ABL-ASS is present on 69% of the disease-bearing chromosomes among affected Jewish individuals and on only 1% of control Jewish chromosomes (chi 2 = 91.07, P much less than .001). The allelic association between this extended haplotype and DYT1 predicts that these three genes lie within 1-2 cM of each other; on the basis of obligate recombination events, the DYT1 gene is centromeric to ASS. Furthermore, this allelic association supports the idea that a single mutation event is responsible for most hereditary cases of dystonia in the Jewish population. Of the 53 definitely affected typed, 13 appear to be sporadic, with no family history of dystonia. However, the proportion of sporadic cases which potentially carry the A12 haplotype at ASS (8/13 [62%]) is similar to the proportion of familial cases with A12 (28/40 [70%]). This suggests that many sporadic cases are hereditary, that the disease gene frequency is greater than 1/15,000, and that the penetrance is lower than 30%, as previously estimated in this population. Most affected individuals were heterozygous for the ABL-ASS haplotype, a finding supporting autosomal dominant inheritance of the DYT1 gene. The ABL-ASS extended-haplotype status will provide predictive value for carrier status in Jewish individuals. This information can be used for molecular diagnosis, evaluation of subclinical expression of the disease, and elucidation of environmental factors which may modify clinical symptoms.

Alleles↗
PubMed1992

Ethnic differentiation at VNTR loci, with special reference to forensic applications.

Allele-rich VNTR loci provide valuable information for forensic inference. Interpretation of this information is complicated by measurement error, which renders discrete alleles difficult to distinguish. Two methods have been used to circumvent this difficulty--i.e., binning methods and direct evaluation of allele frequencies, the latter achieved by modeling the data as a mixture distribution. We use this modeling approach to estimate the allele frequency distributions for two loci--D17S79 and D2S44--for black, Caucasian, and Hispanic samples from the Lifecodes and FBI data bases. The data bases are differentiated by the restriction enzyme used: PstI (Lifecodes) and HaeIII (FBI). Our results show that alleles common in one ethnic group are almost always common in all ethnic groups, and likewise for rare alleles; this pattern holds for both loci. Gene diversity, or heterozygosity, measured as one minus the sum of the squared allele frequencies, is greater for D2S44 than for D17S79, in both data bases. The average gene diversity across ethnic groups when PstI (HaeIII) is used is .918 (.918) for D17S79 and is .985 (.983) for D2S44. The variance in gene diversity among ethnic groups is greater for D17S79 than for D2S44. The number of alleles, like the gene diversity, is greater for D2S44 than for D17S79. The mean numbers of alleles across ethnic groups, estimated from the PstI (HaeIII) data, are 40.25 (41.5) for D17S79 and 104 (103) for D2S44. The number of alleles is correlated with sample size. We use the estimated allele frequency distributions for each ethnic group to explore the effects of unwittingly mixing populations and thereby violating independence assumptions. We show that, even in extreme cases of mixture, the estimated genotype probabilities are good estimates of the true probabilities, contradicting recent claims. Because the binning methods currently used for forensic inference show even less differentiation among ethnic groups, we conclude that mixture has little or no impact on the use of VNTR loci for forensics.

Alleles↗
PubMed1992

A note on Hardy-Weinberg equilibrium of VNTR data by using the Federal Bureau of Investigation's fixed-bin method.

To fully utilize the information of VNTR data for forensic inference, the probability of observing the matching suspect and evidentiary profile in a reference population is estimated, usually by assuming independence of alleles within and between loci. This assumption has been challenged on the basis of the observation that there is frequently an excess of single-band phenotypes (SBP) in forensic data bases, which could indicate lack of independence. Nevertheless, another explanation is that the excess SBP are artifacts of laboratory methods. In this report we examine the excess of SBP for three VNTR loci studied by the FBI (D17S79 and D2S44, for blacks, and D14S13, for Caucasians). The FBI claims that the excess is due to the effect of null alleles; the null alleles are suspected to be too small to be detected. We estimate the frequency of null alleles for two loci (D17S79 and D14S13) by comparing, for these loci, the data from the FBI data base and the data from the Lifecodes data base. These comparisons yield information on small fragments because Lifecodes uses the restriction enzyme PstI, which yields larger fragments than does HaeIII, which the FBI uses. For D17S79 in blacks, we estimate a null allele frequency of 4.4%, and, for D14S13 in Caucasians, we estimate a frequency of 3.0%. The null-allele frequency for D2S44 in blacks is derived similarly, again being based on analyses of DNA cut with HaeIII and PstI; our estimate of the null-allele frequency for this locus is 1.5%.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1992

Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis.

Nonsyndromic cleft lip with or without cleft palate (CL +/- P) is traditionally recognized as a multifactorial threshold trait (MFT). Recently, however, evidence for the involvement of a major gene in the etiology of CL +/- P has been reported. To assess the potential for major-gene involvement in the etiology of this trait, familial recurrence patterns from several family studies of CL +/- P were reanalyzed. The recurrence patterns in first-degree relatives of CL +/- P probands were found to be compatible with the expectations for either an MFT or a generalized single-major-locus (gSML) trait. The use of multiple thresholds based on proband sex, defect bilaterality, or palatal involvement did not help to discriminate between these models. However, the pattern of recurrence among MZ twins and more remote relatives of CL +/- P probands is not consistent with gSML inheritance but is compatible with either an MFT model or a model specifying multiple interacting loci. For such a model, no single locus can account for more than a sixfold increase in risk to first-degree relatives. These findings have important implications with regard to the feasibility of detecting linkage to loci conferring susceptibility to CL +/- P.

Cleft Lip↗
PubMed1991

No association between an allele at the D2 dopamine receptor gene (DRD2) and alcoholism.

OBJECTIVE: --We attempted to replicate a positive allelic association between the A1 allele of DRD2 (the D2 dopamine receptor locus) and alcoholism that has been reported. DESIGN: --We compared allele frequencies at the previously described Taq I restriction fragment length polymorphism system of DRD2 in alcoholics and random population controls. SUBJECTS: --The alcoholic subjects were 44 unrelated white individuals, diagnosed by direct structured interview to have alcohol dependence (by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria). The subjects in our random population control group (N = 68) were also white. RESULTS: --For the control group, allele frequencies at DRD2 were 0.20 (A1) and 0.80 (A2). For the alcoholic group overall, allele frequencies were 0.23 (A1) and 0.77 (A2). There were no significant differences in allele frequencies at the DRD2 locus between alcoholics and controls. The allele frequencies in both groups agreed closely with those observed in most previously described control populations. Subtyping the alcoholic group according to presence or absence of family history of alcoholism, presence or absence of antisocial personality disorder, age of onset, presence or absence of physical withdrawal symptoms, or recent alcohol consumption (as a measure of severity) did not in any case reveal significant differences in allele frequencies. CONCLUSION: --We were not able to replicate the results previously reported. We conclude that our data do not support an allelic association between the A1 allele at DRD2 and alcoholism.

Adult↗
PubMed1991

Developments in gene mapping with linkage methods.

Recent developments in the application of linkage analysis to gene mapping are reviewed. Advances in computational efficiency, through vectorization and parallelization of computer programs, are described. Some developments in methods for mapping the genes for non-mendelian (quantitative and discrete) traits are discussed.

Animals↗
PubMed1991

Estimation of morbid risk and age at onset with missing information.

Investigators of genetic illnesses are currently employing life-table techniques to estimate the lifetime risk of disease and the age-at-onset distribution. This methodology assumes that onset ages are known for affected individuals and that censoring ages are known for unaffected individuals. We extend these methods to incorporate affected individuals with unknown onset ages and unaffected persons with unknown censoring ages and illustrate how conventional life-table methods can produce seriously biased estimates, particularly of lifetime risk. The methodology is not restricted to genetic illnesses and can be applied to more complex illnesses with unknown etiology. We present an example for Huntington disease, which is generally assumed to be a Mendelian autosomal dominant disease, yielding estimates of lifetime risk of .503 +/- .70 and mean onset age of 47.7 +/- 3.1 years for offspring with a single affected parent. When conventional life-table techniques are employed, these estimates are .238 +/- .032 and 43.2 +/- 2.2.

Age Factors↗
PubMed1991

Genetic analysis of breast cancer in the cancer and steroid hormone study.

The familial risk of breast cancer is investigated in a large population-based, case-control study conducted by the Centers for Disease Control. The data set is based on 4,730 histologically confirmed breast cancer cases aged 20 to 54 years and on 4,688 controls who were frequency matched to cases on the basis of both geographic region and 5-year categories of age, and it includes family histories, obtained through interviews of cases and controls, of breast cancer in mothers and sisters. Segregation analysis and goodness-of-fit tests of genetic models provide evidence for the existence of a rare autosomal dominant allele (q = .0033) leading to increased susceptibility to breast cancer. The effect of genotype on the risk of breast cancer is shown to be a function of a woman's age. Although, compared with noncarriers, carriers of the allele appear to be at greater risk at all ages, the ratio of age-specific risks is greatest at young ages and declines steadily thereafter. The proportion of cases predicted to carry the allele is highest (36%) among cases aged 20-29 years. This proportion gradually decreases to 1% among cases aged 80 years or older. The cumulative lifetime risk of breast cancer for women who carry the susceptibility allele is predicted to be high, approximately 92%, while the cumulative lifetime risk for noncarriers is estimated to be approximately 10%.

Adult↗
PubMed1991

Estimation of allele frequencies for VNTR loci.

VNTR loci provide valuable information for a number of fields of study involving human genetics, ranging from forensics (DNA fingerprinting and paternity testing) to linkage analysis and population genetics. Alleles of a VNTR locus are simply fragments obtained from a particular portion of the DNA molecule and are defined in terms of their length. The essential element of a VNTR fragment is the repeat, which is a short sequence of basepairs. The core of the fragment is composed of a variable number of identical repeats that are linked in tandem. A sample of fragments from a population of individuals exhibits substantial variation in length because of variation in the number of repeats. Each distinct fragment length defines an allele, but any given fragment is measured with error. Therefore the observed distribution of fragment lengths is not discrete but is continuous, and determination of distinct allele classes is not straightforward. A mixture model is the natural statistical method for estimating the allele frequencies of VNTR loci. In this article we develop nonparametric methods for obtaining the distribution of allele sizes and estimates of their frequencies. Methods for obtaining maximum-likelihood estimates are developed. In addition, we suggest an empirical Bayes method to improve the maximum-likelihood estimates of the gene frequencies; the empirical Bayes procedure effects a local smoothing. The latter method works particularly well when measurement error is large relative to the repeat size, because the estimated distribution of allele frequencies when maximum likelihood is used is unreliable because of an alternating pattern of over- and underestimation. We define alleles and estimate the allele frequencies for two VNTR loci from the human genome (D17S79 and D2S44), from data obtained from Lifecodes, Inc.

Alleles↗
PubMed1991

A note on multiple testing procedures in linkage analysis.

Controversy over the impact of multiple testing procedures in linkage analysis is reexamined in this report. Despite some recent claims to the contrary, it is shown that testing multiple markers decreases the posterior false-positive rate among significant tests, rather than increasing it; this is true whether the trait of interest is simply monogenic or complex, or even if the genetic model is misspecified. However, if the true mode of inheritance is complex, or if the genetic model is misspecified, the power to obtain a significant result when linkage is present may be reduced, while the significance level is not, leading to an inflation of the posterior false-positive rate. Furthermore, the posterior false-positive rate increases with decreasing sample size and may be unacceptably high for very small samples. By contrast, testing multiple genetic models, by varying either mode-of-inheritance parameters or diagnostic categories, does lead to an inflation of the posterior false-positive rate. A conservative correction for this case is to subtract log10t from the obtained maximum lod score, where t different genetic and/or diagnostic models have been tested.

Genetic Linkage↗