一种病例对照家系资料的家庭相关统计分析方法

目的 提出一种分析病例对照家系资料家庭相关的统计方法。方法 同时建立先证者疾病状态和给定先证者疾病状态条件下亲属疾病状态的边际均数回归模型和亲属的边际关联回归模型,联合条件OR值和边际OR值评价家庭相关。结果 该模型参数解释符合抽样设计的特点,在评价危险因素作用上能充分利用信息,因此有较高效能。此外,该法具有GEE2方法估计家庭相关的所有其他优点。结论 该法用于病例对照家系资料估计疾病的家庭相关,简单、方便、有效。     

应用边际回归模型研究原发性肝癌的家庭相关

目的探讨泰兴市原发性肝癌的家庭聚集性。方法采用病例对照家系设计收集家系资料，应用边际回归模型方法分析亲属间肝癌的家庭相关大小和模式。结果肝癌病例的亲属比对照亲属有更高的疾病风险。调整了乙肝表面抗原后，亲属间的相关不再有统计学意义。结论边际回归模型可用于家系资料，研究表明肝癌存在家庭聚集性，HBV感染在肝癌的家庭聚集性中起着很重要的作用。     

Ⅱ型糖尿病的家庭聚集性研究

目的　通过对Ⅱ型糖尿病家庭聚集性的分析,探讨遗传因素在糖尿病患者一级亲属成员发病中所起的作用及其相对危险度。方法　采用以人群为基础的遗传流行病学病例对照研究方法,对３６３ 例Ⅱ型糖尿病先证者家系及２９１ 例人群对照家系进行了调查。结果　先证者家系一级亲属糖尿病的患病率为３ ．９４ ％ ,对照组一级亲属为１ ．０９ ％ ,相对危险度为３ ．６２ ,各组血缘亲属的相对危险度均在３ ．０ 以上;糖尿病先证者诊断时年龄越轻,其一级亲属的糖尿病患病率和相对危险度越高,其家系内发生多例糖尿病病例的可能性越大。结论　Ⅱ型糖尿病具有明显的家庭聚集倾向,其一级亲属对糖尿病的遗传易感性较高,是糖尿病预防和控制的重点人群。     

淮安地区食管癌遗传流行病学研究

[目的]了解遗传因素在淮安地区食管癌发病中的作用及食管癌的遗传模式.[方法]采用以人群为基础的病例对照家系研究,收集97对淮安当地原发性食管癌患者及其对照的家系资料,调查这些家系所有一级亲属的肿瘤发病率;应用多因素非条件Logistic回归估计食管癌家族史的发病风险,Li-Mantel-Gart法计算食管癌的分离比,Penrose法估计遗传模式,Falconer法计算遗传度.[结果]淮安地区食管癌先证者与对照的食管癌家族史差异有统计学意义,先证者家系的一级亲属食管癌患病风险显著高于对照家系,其同胞分离比为0.026(95%CI:0.0003～0.028),Ⅰ级亲属食管癌的遗传度为(24.769±7.038)%.[结论]淮安地区食管癌具有明显的家族聚集性,遗传因素在淮安地区食管癌病因中占一定比重,其遗传模式呈现多基因遗传方式.     

2型糖尿病遗传病因的流行病学研究

对３６３例２型糖尿病先证者家系及２９１例人群对照家系进行了以人群为基础的遗传流行病学病例－对照研究。结果显著的：糖尿病先证者一级亲属（父母、同胞、子女）的累积发病率为３．９４％,对照组一级亲属１．０９％,相对危险度（ＲＲ）为３．６２,差异有非常显著性意义（χ２＝３６．５４,Ｐ＜０．００１）;无论男性或女性一级亲属,先证者组的累积发病率均非常显著地高于人群对照组;诊断时年龄＜５５岁先证者的一级亲属,其糖尿病累积发病率和相对危险度均显著高于诊断年龄＞５５岁组。二项分布显示先证者一级亲属中２型糖尿病的分布呈明显的家庭聚集性,先证者一级亲属的遗传度为４０．４％（男性４２．６％,女性３８．６％）;２型糖尿病在同胞中的分离比为０．０３２,显著低于０．２５,不符合单基因遗传的特征。     

食管癌的遗传流行病学研究

目的：探讨遗传因素与食管癌的关系。方法：通过遗传流行病学病例对照研究方法,对海安县２６５个食管癌先证者家系和２６５个对照家系进行分离比、遗传度估计。结果：食管癌先证者一级亲属的发病率（５．３８％）明显高于对照一级亲属的发病率（２．８１％）,食管癌遗传度为２４．２４％,分离比为０．１２１４,小于０．２５,属多基因遗传疾病。结论：海安县食管癌的病因中,遗传因素起重要作用。     

病例对照家系设计中样本含量的估算

目的：探讨病例对照家系设计中样本含量的估算方法及影响因素。方法：在评价病例亲属和对照亲属再发风险的前提下，考虑亲属疾病表型的家庭相关，估计样本含量。结果：用实例说明了病例对照家系设计中样本含量估计方法的应用与影响因素和样本含量的关系。结论：家庭相关越大，需要的家庭数越多；家庭中亲属成员个数越多，需要的家庭数越少。     

核心家系中删失性状遗传方差分量模型的研究

目的研究核心家系资料中删失性状的遗传方差分量模型,评价环境因素和遗传因素对删失性状的影响。方法应用多变量脆弱模型研究删失性状的遗传方差分量,基础模型选用Cox比例危险模型,MCMC方法用于参数估计,原发性肝癌核心家系发病年龄资料的分析说明了该方法的实际应用。结果实例分析结果符合专业解释,该模型对生存时间分布没有要求因而有更广泛的适用性。结论基于Cox回归模型的遗传方差分量模型可用于家系资料,研究生存时间资料的遗传和环境因素的作用。     

慢性阻塞性肺部疾病的家族聚集性分析

为了判断慢性阻塞性肺部疾病（ＣＯＰＤ）的家族聚集性，探讨遗传因素对ＣＯＰＤ发病的影响，分析了２０６对核心家系的资料。结果表明：ＣＯＰＤ的发病具有家族聚集性。ＣＯＰＤ先证者的亲属（父母、兄弟姐妹）患ＣＯＰＤ的危险性增加，是对照家系亲属（父母、兄弟姐妹）的２．０７倍。除母亲之外，两家系父亲间，兄弟间及姐妹间患ＣＯＰＤ危险性的差异均具有显著性。故ＣＯＰＤ先证者的亲属对ＣＯＰＤ的易感性比对照的亲属高，说明遗传因素是ＣＯＰＤ的危险因素之一。     

2型糖尿病先证者发病年龄对遗传表型影响的研究

目的探讨2型糖尿病（DM）先证者发病年龄对糖耐量正常一级亲属的胰岛素抵抗（IR）表型及胰岛β细胞功能的影响。方法选择186个2型DM核心家系中186例2型DM先证者和489例糖耐量正常的一级亲属。根据先证者发病年龄的四分位数，分别选取最低四分位数发病年龄的先证者（发病年龄〈42岁）的一级亲属127例（为一级亲属1组）和最高四分位数发病年龄的先证者（发病年龄〉55岁）的一级亲属118例（为一级亲属2组）进行研究。应用HOMA—IR，△I30／△G30（包括△I30.△G30^-1．HOMA—IR^-1）分别评估胰岛素敏感性和胰岛β细胞功能。结果一级亲属1组的腰臀围比、收缩压、甘油三酯、HOMA-IR均高于一级亲属2组，△I30/△G30△I30.△G30^-．HOMA-IR^-1均低于一级亲属2组，差别有统计学意义（P〈0．05或0．01）。结论早发2型DM先证者的糖耐量正常一级亲属可能具有更明显的IR表型特点和β细胞功能降低。     

Estimating effects of proband characteristics on familial risk: II. The association between age at onset and familial risk in the Maryland schizophrenia sample.

In this report we apply methods outlined in the companion paper [Liang, Genet Epidemiol 8:329-338, 1991] to study the association between proband age at onset and familial risk among first-degree relatives of 374 schizophrenic probands. The analyses take into consideration the potential problems of censoring and correlation of age at onset within families. All analyses were done by gender of the proband; age at onset was dichotomized. The results of the analyses of the male probands suggest that there is an increased risk of schizophrenia among the relatives of male probands who have an onset prior to age 17 when compared to relatives of male probands who have an onset later than 16. We did not find an association between age at onset and familial risk among the female probands, but this may be due to the smaller number of female probands and the lower power associated with the analyses.     

Familial aggregation of diabetes and hypertension in a case-control study of colorectal neoplasia

Familial aggregation of diseases potentially associated with metabolic syndrome (diabetes mellitus, hypertension, and cardiovascular diseases) was assessed in a colonoscopy-based case-control study of colorectal neoplasia in Toronto and Ottawa, Canada, in 1993-1996. Each familial disease was analyzed by logistic regression using generalized estimating equations. Case probands had incident adenomatous polyps (n = 172) or incident (n = 25) or prevalent (n = 132) colorectal cancer (CRC), while control probands (n = 282) had a negative colonoscopy and no history of CRC or polyps. Significant effect modification was evident in the data, with the strongest positive associations between familial diabetes and colorectal neoplasia among older probands with symptoms (parents: odds ratio (OR) = 2.4, 95% confidence interval (CI): 1.2, 4.8; siblings: OR = 5.8, 95% CI: 2.6, 13.3). Familial hypertension was also associated with colorectal neoplasia among probands with symptoms (OR = 1.7, 95% CI: 1.1, 2.6). In stratified analyses, familial diabetes, hypertension, and stroke were positively associated with adenomatous polyps in subgroups of probands who were older and/or had symptoms, while only familial diabetes was possibly associated with CRC. Associations in other proband groups may have been obscured by high cumulative incidence of parental CRC. Family studies are needed to understand the contribution of specific environmental and genetic factors in accounting for the disease aggregations.     

Evidence for age-specific genetic relative risks in lung cancer

Recent studies of familial aggregation suggest that family history of lung cancer among first-degree relatives is associated with increased risk for early-onset, but not late-onset, lung cancer. To assess whether this could be explained by variability in genetic relative risk across age, segregation analysis was performed on the Louisiana Lung Cancer Dataset. This data set consisted of 337 probands who died of lung cancer between 1976 and 1979 and their first-degree relatives. A variation of the Cox proportional hazards model was used that allowed estimation of age- and genotype-specific incidence rates, from which the authors obtained estimates of age-specific genetic relative risks. The best-fitting model included an autosomal dominant locus (allele frequency, 0.043), with carrier-to-noncarrier relative risks that exceeded 100 for ages less than 60 years and declined monotonically to 1.6 by age 80. The hypothesis of proportional genetic relative risk across age was rejected (p = 0.009). The estimated proportion of persons with lung cancer who carry the high-risk allele exceeds 90% for cases with onset at age 60 years or less and decreases to approximately 10% for cases with onset at age 80 years or older. These findings support previous evidence of a major susceptibility locus for lung cancer and suggest that linkage studies should preferentially recruit young lung cancer cases and their relatives.     

An analytical method for assessing patterns of familial aggregation in case-control studies.

This paper describes an analytical method that is used to assess patterns of disease aggregation within family based on family history information collected in case-control studies. In such a study, cases and controls are thought of as probands whose relatives are identified, and relatives' phenotypes and other covariates such as age, sex, and genealogical relationship with the probands are recorded. By modeling the dependence of relatives' phenotypes on case-control status and other covariates, this method yields adjusted odds ratios that quantify familial aggregation. The estimated standard errors are obtained for statistical inference since the method acknowledges the potential correlations between relatives' phenotypes by using the estimating equations technique. In population-based case-control studies, the estimates and statistical inferences are generalizable to the general population. To illustrate this method, we analyzed a case-control study of colorectal cancer involving 5,190 relatives of 792 cases and 4,478 relatives of 680 population-based controls conducted in Hawaii. Although detailed results will be presented elsewhere, the colorectal cancer was found to aggregate within family with an odds ratio of 2.74 (95% confidence interval (CI): 1.78-4.21). Among parents, the odds ratio for familial aggregation was 2.38 (95% CI: 1.25-4.54). The corresponding value for siblings was 3.09 (95% CI: 1.87-5.11). It was also found that the odds ratio increases from about 2.00 for relatives of the probands who were 50 years or older to 7.66 and 12.84 for relatives of the probands who were between 40 and 50 years and under 40 years, respectively, suggesting that the familial aggregation of colorectal cancer decreases as probands' age increases.     

Familial risk of cancer among randomly selected cancer probands

Several investigators have reported that relatives of lung cancer probands have a greater-than-normal likelihood for developing some form of cancer. To evaluate whether this familial risk is general for probands with cancer at any site or limited to lung cancer probands, we did a case-control study in which probands having cancer affecting any body site were identified and their pedigree data were tabulated. Telephone interviews and a mailed questionnaire were used to obtain cancer histories and environmental exposures on the families of 41 lung cancer probands, 105 probands with cancer other than lung, and 127 spouse families. Cumulative tobacco exposure (P less than .05), occupational hazards (P less than .005), and age of the family relatives (P less than .0001) were found to be statistically significant predictors of cancer risk. With consideration given for these variables, we determined that siblings of lung cancer probands were at slightly greater risk of cancer of any kind (odds ratio [OR] = 1.43, P = .06) than siblings in the control group. Much of the elevated risk was attributable to an excess of lung cancer (OR = 2.49, P = .06). Siblings of non-lung/non-breast cancer probands were also determined to be at increased risk of lung cancer as well (OR = 1.61, P = .06). For parents, the risk was lower, although parental information may have been underreported.     

Etiologic heterogeneity in alcoholism

Etiologic heterogeneity in alcohol abuse was evaluated in 195 extended pedigrees, comprising 288 nuclear families of 140 male and 55 female Caucasian American hospitalized alcoholics. Previous adoption studies in Sweden demonstrated differential heritability of two patterns of alcohol abuse in men: type-2 alcoholism exhibited early onset of abuse associated with criminal behavior, while type-1 abuse began at a later age, uncomplicated by antisocial traits. Alcohol abuse in female Swedish adoptees was relatively homogeneous and similar to the late-onset, type-1 abuse. The notion of etiologic heterogeneity, as suggested by the Stockholm Adoption Studies, was examined in the American pedigrees by contrasting the models of familial transmission of susceptibility to alcoholism obtained via segregation analyses of families of male versus female probands. Families of male probands demonstrated significant familial resemblance, accounted for by a multifactorial-polygenic background in addition to a major (gene) effect. In contrast, familial resemblance in the pedigrees of female probands was attributed solely to a multifactorial-polygenic effect. We considered whether some families of male alcoholics were similar to families of female probands, who expressed type-1 abuse predominantly. Pedigrees of male probands were separated in two groups: (1) "female-like" families had a better likelihood for the model obtained for families of female probands than the one for families of all male probands, (2) "male-like" families had a better likelihood for the model of familial transmission describing families of all male probands. A statistically significant difference in the pattern of familial transmission was observed between the "male-like" and "female-like" groups. Discriminant function analysis of alcohol-related symptoms showed that the familial subtypes differed in clinical features as well. Alcohol abuse by male relatives in "male-like" families was characterized by the early onset of inability to abstain entirely from alcohol or lack of desire to stop drinking; in contrast, abuse in "female-like" families was characterized by late onset of guilt feelings and loss of control over binge drinking.     

Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study

BACKGROUND AND PURPOSE: Stroke occurs infrequently in young adults. While a familial basis for older onset stroke is well established, the extent of familial clustering in young-onset stroke is unknown. To address this issue, we compared the frequency of stroke in relatives of stroke cases to that in relatives of controls across different ages and by stroke subtype. METHODS: Through a population-based case-control study of stroke, we identified 487 women aged 15-49 years with ischemic stroke and 615 women without stroke matched by age and geographic region. Family history of stroke was collected for 5,749 relatives (parents and siblings) of case and control probands by standardized interview. RESULTS: Strokes were reported in 149 relatives of case patients and 119 relatives of controls. Siblings of stroke case patients had more than four times the risk of stroke compared to siblings of controls (OR, 4.17; 95% CI, 1.9-8.8) and mothers of stroke case patients had twice the risk of stroke compared to mothers of control subjects (OR, 2.02; 95% CI, 1.4-3.0). The association between stroke in probands and family history of stroke was strongest among women aged 15-24 years (OR, 2.5; 95% CI, 0.4-15.1), and diminished with increasing proband age (OR, 1.6; 95% CI, 0.8-3.3 among women 25-34 years and OR, 1.5; 95% CI, 1.1-1.9 among women 35-49 years; P<0.0001 for trend). CONCLUSIONS: We conclude that young-onset stroke aggregates in families and that the magnitude of aggregation increases with decreasing proband age.     

Epidemiological study of genetic and environmental factors in asthma, bronchial hyperresponsiveness and atopy. Protocol and potential selection bias

BACKGROUND: The EGEA study combines a case-control study and a family study to assess genetic and environmental risk factors and their interactions for asthma, bronchial hyperresponsiveness and atopy. Information is scanty regarding potential selection biases, in particular regarding familial ressemblance in epidemiological surveys of this kind. METHODS: Asthmatic probands (adult and paediatric) were recruited in chest clinics of six clinical centres. Controls were mostly population-based (electoral rolls) for adults and recruited in surgery departments for children. RESULTS: The population examined includes 348 nuclear families ascertained by one asthmatic and 416 controls, totalling 1847 subjects (EGEA I) and an additional sample of 40 families ascertained by two asthmatic siblings (EGEA II). Potential biases for the various types of analyses have been studied. Quantification of the consequences of the greater participation of probands with a parental history of asthma shows it does not introduce a major bias in the estimates of familial resemblance. Cases and controls showed a good comparability regarding sex, age, area of residence and familial geographical origin, allowing proper associations studies for environmental and candidate genetic factors. CONCLUSIONS: The case-control component of the study will allow to perform studies on environmental factors and association studies for various genetic polymorphisms. Using the family base collected, segregation and genetic linkage/association analyses with DNA markers may be performed.