Validation of family history data in cancer family registries

BACKGROUND: Although family history information on cancer is used to infer risk of the disease in population-based, case-control, cohort, or family-based studies, little information is available on the accuracy of a proband's report. In this study, we sought to determine the validity of the reporting of family history of cancer by probands in population-based and clinic-based family registries of breast, ovarian, and colorectal cancers. METHODS: To assess the accuracy of probands' reported family history of cancer in their relatives, we compared the family history from the personal interview of each proband to a reference standard that included pathology reports, self-reports, or death certificates on the relatives. Our study included 1111 families that accounted for 3222 relatives who were verified. To account for within-family correlations in the responses, we used a generalized estimating equation approach. RESULTS: The probability of agreement between the proband-reported cancer status in a relative with the reference standard varied by cancer site and by degree of relationship to the proband. This probability for first-degree relatives was 95.4% (95% confidence interval [CI]=92.6-98.3) for female breast cancer; 83.3% (95% CI=72.8-93.8) for ovarian cancer; 89.7% (95% CI=85.4-94.0) for colorectal cancer; and 79.3% (95% CI=70.0-88.6) for prostate cancer. CONCLUSIONS: We found high reliability of probands' reporting on most cancer sites when they reported on first-degree relatives and moderate reliability for their reporting on second- and third-degree relatives. Overreporting of cancer was rare (2.4%). Race or ethnicity and gender of the proband did not influence the accuracy of reporting. However, degree of relationship to the proband, type of cancer, age at diagnosis of the proband, and source of ascertainment of probands were statistically significant predictors of accuracy of reporting.     

Discordance Between Sibling and Parent Reports of the Impact of Chronic Illness and Disability on Siblings

This study compared sibling and parent reports of sibling adjustment to chronic illness/developmental disability (CI/DD) in 51 siblings (ages 8 to 13). Discordance between sibling and parent reports on the Sibling Perception Questionnaire was common, with parents tending to report more sibling adjustment problems than did siblings. Siblings who reported more problems than parents tended to be younger and male. There was a trend for parents who reported more problems than siblings to also report greater negative impact of CI/DD on family social functioning than other parents. Findings highlight the importance of obtaining sibling self-reports in research and clinical settings.     

Discordance Between Sibling and Parent Reports of the Impact of Chronic Illness and Disability on Siblings

This study compared sibling and parent reports of sibling adjustment to chronic illness/developmental disability (CI/DD) in 51 siblings (ages 8 to 13). Discordance between sibling and parent reports on the Sibling Perception Questionnaire was common, with parents tending to report more sibling adjustment problems than did siblings. Siblings who reported more problems than parents tended to be younger and male. There was a trend for parents who reported more problems than siblings to also report greater negative impact of CI/DD on family social functioning than other parents. Findings highlight the importance of obtaining sibling self-reports in research and clinical settings.     

Validity of family history for the diagnosis of dementia among siblings of patients with late-onset Alzheimer's disease

We examined 180 siblings of 127 probands with probable or possible Alzheimer's dementia (AD) in a family study of AD. The overall sensitivity of a simple family history questionnaire was 64% and the specificity was 84%. Sensitivity improved 90–100% with minimal decline in specificity when we considered clinic-based vs. Population survey patients. Higher education among informants and the availability of a spouse or a sibling as informant significantly increased sensitivity. Awareness of such factors may improve the yield of the family history in AD using a simple questionnaire. Genet. Epidemiol. 15:215–223, 1998. © 1998 Wiley-Liss, Inc.     

Regressive logistic modeling of familial aggregation for asthma in 7,394 population-based nuclear families

The aim of this population-based study was to determine whether asthma aggregates in families, and if so, whether aggregation was consistent with environmental and/or genetic etiologies. Data were from 7,394 nuclear families (41,506 individuals) from the 1968 Tasmanian Asthma Survey, in which all Tasmanian schoolchildren born in 1961 were surveyed by respiratory questionnaire completed by their parents. Similar data were obtained for parents and siblings of probands. For a child, having ever had asthma was predicted by a parent or sibling having ever had asthma; odds ratio (OR) = 3.13 (95% confidence interval [CI] 2.82–3.48) for mother, 2.99 (2.69–3.32) for father, and 3.47 (3.23–3.72) for a sibling. Regressive logistic modeling showed that, in addition to parent-offspring effects, the data were consistent with the existence of an unmeasured factor shared by siblings, evident in 15% (SE 2%) of families and associated with a conditional OR of 9.68 (8.27–11.32). Familial aggregation was best described by a general oligogenic model with non-Mendelian transmission probabilities. Of the Mendelian models, a codominant model with an allele frequency of 16% (SE 0.3%) was preferred. Under a dominant model there was evidence for additional parent-offspring and sibling effects of similar magnitude. It is unlikely that there is one major loci influencing asthma susceptibility; the overall effects of asthma genes in the population are more likely to be inherited codominantly, at least for the majority of loci of major etiological importance. The role of environmental factors in explaining part of familial aggregation for asthma cannot be ruled out, as major triggers of asthma attacks are familial. Genet. Epidemiol. 14:317–332,1997. © 1997 Wiley-Liss, Inc.     

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.     

Genetic epidemiologic methods to screen for matrilineal inheritance in mitochondrial disorders

We propose a method to screen for the matrilineal inheritance in mitochondrial disorders by comparing the risk of disease in a person whose mother is affected or whose maternal grandmother or aunt or uncle is affected to the risk of disease in a person whose father is affected or whose paternal grandmother or aunt or uncle is affected using a modification of the reconstructed cohort design. Sampling of pedigrees is accomplished via probands and must not be influenced by family history. The cohort of the proband's offspring, and offspring of the proband's siblings, can be analyzed using survival analysis, Cox proportional hazards model, Bonney's [(1986) Biometrics 42:611–625] model, and Liang's [(1991) Genet Epidemiol 8:329–338] model. Mitochondrial transmission can be distinguished from X-linked transmission by examining sex-specific patterns of disease expression in matrilineally transmitted diseases. To illustrate our epidemiologic method, we apply our screening method to pedigrees of two disorders which have been proposed to have a mitochondrial DNA component to their inheritance. © 1996 Wiley-Liss, Inc.     

Information Needs of the Siblings of Critically Ill Children

This study explored parental and sibling perceptions and feelings about sibling information needs during a pediatric admission to an intensive care unit (ICU). Using a qualitative research design, patents (n = 14) and school-age siblings (n = 12) of children who were patients in ICU were interviewed using open-ended questions. Themes of information that the parents report having given to the siblings were similar to the themes that siblings report having heard. However, parents reported that the siblings had numerous questions about the reasons for hospitalization and expectations for the future of the family. The findings indicate that parents may neither be aware of the effects of the ICU experience on the siblings nor have the knowledge and skill to assist them. Parents may need counseling to increase their awareness of the siblings' need for information and teaching to increase skill in providing the information.     

病例对照家系研究中发病年龄的家庭相关分析方法

目的 探讨失效时间的关联测量和病例对照家系研究中发病年龄家庭相关的分析方法。方法 分层Cox模型用于估计病例对照家系研究中肝癌发病年龄的交叉比。结果 显示先证者和父亲、母亲、同胞间发病年龄的家庭相关有统计学意义，而先证者和配偶间发病年龄的家庭相关没有统计学意义。结论 分层Cox模型可用于病例对照家系研究中发病年龄的家庭相关估计。     

Patients' sibling history was sensitive for hypertension and specific for diabetes

OBJECTIVE: We examined the analytic validity of reported family history of hypertension and diabetes among siblings in the Seychelles. STUDY DESIGN AND SETTING: Four hundred four siblings from 73 families with at least two hypertensive persons were identified through a national hypertension register. Two gold standards were used prospectively. Sensitivity was the proportion of respondents who indicated the presence of disease in a sibling, given that the sibling reported to be affected (personal history gold standard) or was clinically affected (clinical status gold standard). Specificity was the proportion of respondents who reported an unaffected sibling, given that the sibling reported to be unaffected or was clinically unaffected. Respondents gave information on the disease status in their siblings in approximately two-thirds of instances. RESULTS: When sibling history could be obtained (n=348 for hypertension, n=404 for diabetes), the sensitivity and the specificity of the sibling history were, respectively, 90 and 55% for hypertension, and 61 and 98% for diabetes, using clinical status and, respectively, 89 and 78% for hypertension, and 53 and 98% for diabetes, using personal history. CONCLUSION: The sibling history, when available, is a useful screening test to detect hypertension, but it is less useful to detect diabetes.     

Event-related potentials in alcoholics and their first-degree relatives

Preliminary results are presented for auditory ERPs recorded from members of alcoholic families during performance of a counting task and a choice reaction task. Alcoholic families included three adult male siblings (alcoholic proband, a second affected sib, and an unaffected sib) and parents. Control families included two adult male sibs and parents. In all experimental conditions, the N100 component was decreased in amplitude for all sibs (affected and unaffected) of the alcoholic families. The latency of the P300 component was increased for both affected and unaffected sibs compared to controls in the counting task, indicating a familial difference irrespective of drinking status. In the choice reaction task, longer P300 latencies were observed among the probands and their affected sibs as compared to their unaffected sibs, suggesting that in this more demanding task, increased latency was associated with a significant drinking history. ERP findings for children of the alcoholic probands are also discussed. The effects of differences in task complexity, drinking variables, and criteria for family selection are considered.     

Estimating the number of potential family members eligible for BRCA1 and BRCA2 mutation testing in a “Traceback” approach

U.S. guidelines recommend BRCA1/2 mutation testing for women diagnosed with high‐grade ovarian cancer (HGOC) to increase recognition of carriers, but most remain unidentified and at risk. Accordingly, an approach termed “Traceback” has been proposed in which probands are retrospectively identified by testing archived pathology specimens, and family members are traced to provide genetic counseling and testing. We used population‐based data to estimate the number of family members who might be contacted through such a program. We used incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate the number of women diagnosed with HGOC from 2005 to 2016, and census data to estimate the number of spouses, offspring, and siblings (both sexes). Using overall survival for HGOC from SEER and all‐cause mortality rates from the Centers for Diseases Control and Prevention, we estimated the number of patients, spouses, offspring, and siblings of HGOC cases living in 2017. Due to the high mortality rate of HGOC, consent from living probands may be possible in only 42% of the cases; consent to test pathology specimens would need to be sought from next of kin for the remainder. In 2017, an estimated 406,919 living next of kin (spouses, siblings, offspring) would be available for potential consent. Testing archived ovarian cancer pathology specimens may enable the identification of BRCA1/2 mutation carriers, but consent from next of kin would be required in in 58% of cases. Although Traceback offers the possibility of identifying unaffected BRCA1/2 mutation carriers, pilot feasibility studies that include assessment of methods to secure consent are needed.     

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.     

胃癌双Y核心家系地区与家庭聚集性研究

目的探讨江苏省扬中市胃癌是否有地区和家庭聚集性。方法利用扬中恶性肿瘤发病登记报告资料和全新设计的双Y核心家系调查资料,对448个胃癌核心家系和437个对照家系,共5242人进行遗传流行病学研究。结果Poisson分布χ     

Temperament and the Quality of Best Friendships: Effect of Same‐Sex Sibling Relationships*

The authors examined whether early adolescents' sibling relationships ameliorate the effects of a difficult temperament on best friendships, exploring whether qualities of early adolescents' sibling relationships would moderate the link between temperamental difficulties and best friendship quality. Data were collected at two points. At first collection, parents provided temperament ratings for 73 later‐born siblings (M= 7 years ). Five years later, adolescents provided information about support and discord present in their best friendships and older siblings provided information about the warmth and conflict in their same‐sex sibling dyads. The hypothesized moderating effect of the sibling relationship was found only for early adolescent girls. Support and discord in girls' best friendships was negatively and positively predicted, respectively, by level of temperamental difficulty only when relationships with their older sisters were lower in warmth or higher in conflict. Implications for understanding and improving early adolescents' closest friendships are discussed.     

Sibling empathy and behavioural adjustment of children with chronic illness

This study Investigated the relationship of healthy siblings’empathy to the psychosocial adjustment of children with a congenital heart disease (CHD) in 28 sibling dyads aged 3.5-11 years, as well as the perceived quality of sibling Interactions, reported by mothers and children with illness. As in previous studies, children with CHD were reported to have more behaviour problems in the clinical range than either siblings or normative populations. On the basis of a task unconnected with illness issues, siblings were assigned to a high or low empathy group. Children with illness, but not their mothers, saw the siblings with high empathy more positively than those with low empathy. However, the adjustment of the children with illness did not differ between high and low empathy groups. Findings suggest the need to seek children's points of view when studying psychosocial effects of paediatric conditions.     

Familiality of Gender Identity Disorder in Non-Twin Siblings

Familial studies and reports of co-occurrence of gender identity disorder (GID) within a family may help to clarify the question of whether transsexualism is a familial phenomenon. In a sample of 995 consecutive transsexual probands (677 male-to-female [MF] and 318 female-to-male [FM]), we report 12 pairs of transsexual non-twin siblings (nine pairs of MF siblings, two pairs of MF-FM siblings, and one pair of FM siblings). The present study doubles the number of case reports of co-occurrence of transsexualism in non-twin siblings available in the literature. According to our data, the probability that a sibling of a transsexual will also be transsexual was 4.48 times higher for siblings of MF than for siblings of FM transsexual probands, and 3.88 times higher for the brothers than for the sisters of transsexual probands. Moreover, the prevalence of transsexualism in siblings of transsexuals (1/211 siblings) was much higher than the range expected according to the prevalence data of transsexualism in Spain. The study suggests that siblings of transsexuals may have a higher risk of being transsexual than the general population, and that the risk is higher for brothers than sisters of transsexuals, and for siblings of MF than FM transsexuals. Nevertheless, the risk is low.     

Long‐term effects of health investments and parental favoritism: the case of breastfeeding

This paper re‐examines the effects of breastfeeding on long‐term educational outcomes using longitudinal data on siblings. While family‐fixed effects allow controls for all shared family factors, these estimators are sensitive to compensating or reinforcing behaviors by parents. These biases may be particularly important for estimating the effects of parental investment such as breast feeding, where sibling discordance may be difficult to treat as a random outcome and may result in persistence in differential investments between siblings. This paper uses a unique question asked to adolescent siblings about parental favoritism to adjust for potential reinforcing behavior by parents. Standard fixed effects estimates suggest important long‐term educational effects of breastfeeding; however, these effects are uniformly eliminated after focusing on families who treat siblings equally. These findings shed light on the mechanisms linking associations between breastfeeding and longer term outcomes. Copyright © 2010 John Wiley & Sons, Ltd.     

Screening for coeliac disease in families of adults with Type 1 diabetes based on serological markers

The prevalence of coeliac disease (CD) in the adult population is unknown because silent and latent stages do exist. Type 1 diabetes mellitus may be associated with CD because of common genetic background and/or shared pathogenetic mechanisms. We investigated 74 adults with type 1 diabetes (32+/-11 yr, disease duration 13+/-9 yr), 69 parents of diabetic probands (56+/-10 yr), 59 siblings (30+/-11 yr) and 50 healthy controls (35+/-10 yr) for the presence of circulating islet cell antibodies (ICA), anti-glutamic acid decarboxylase antibodies (GADA65), anti-gliadin immunoglobulins A and G (IgA- and IgG-AGA). All patients with raised AGA, performed also IgA anti-endomysium antibody (EmA) indirect immunofluorescence assay. Samples were positive for ICA in 19 diabetics (26%), 4 parents (6%), 4 siblings (7%), 0 controls (p<0.001); for GADA in 34 diabetics (46%), 4 parents (6%), 1 sibling (2%), 0 controls (p<0.001). Twenty-five diabetic patients (34%), 10 parents (14%), 5 siblings (8%), 3 controls (6%) (p<0.001) had raised IgA-AGA (>4.4 mg/l). Four diabetic patients (5%), 5 parents (7%), 0 siblings (0%), 4 controls (8%) had raised IgG-AGA (>18 mg/l). Both IgA- and IgG-AGA were detected in 1 diabetic and 2 parents. The prevalence of ICA, GADA, and IgA-AGA positivity in Type 1 diabetes patients was significantly higher than in controls (p<0.001). Finally, 50 AGA-positive subjects performed EmA test: only 2 of them resulted EmA-positive, a diabetic patient and a sibling. The patient with Type 1 diabetes had a small-bowel biopsy specimen consistent with CD and, as sole evidence of malabsorption, sideropenic anaemia. EmA-positive sibling also showed severe iron deficiency, yet refused endoscopy. We conclude that: 1) CD cannot be diagnosed on the basis of associated IgA- and IgG-AGA alone. Nevertheless, detection of such antibodies is useful, in combination with EmA, in screening for endoscopic biopsy; 2) too high rate of detection of IgA-AGA in Type 1 diabetic patients in comparison with other groups excludes a false positivity of the test itself, while suggests a pathogenetic association of both immunological disorders, perhaps related to abnormal gammadelta TCR-bearing intraepithelial lymphocytes.     

A family study of panic disorder

Panic disorder, as defined by the DSM III diagnostic criteria, was diagnosed in 117 probands for whom age of onset ranged from 10 to 59 years, with a mean of 26.6 years. Diagnosis of parents and siblings was based on interviews with the probands, and only those with “definite” panic disorder by the FISC criteria were considered to be affected. The pattern of concordances for panic across different groups of relatives was estimated concurrently by a log-linear model for binary pedigree data, assuming different values for the cumulative risk. When an adjustment for age was made, based on the age of onset of probands, there was no significant difference between parent-offspring concordance and sibling concordance. There was a negative, but not significant, concordance between spouse pairs. Assuming the lifetime cumulative risk was 1.9% for males and 4.7% for females, values considered appropriate for this population, our model predicted that the presence of an affected parent or sibling incurs an approximately five times increase in the risk of developing panic disorder. Our model assumes in effect that this risk is multiplied for each further affected relative. Although the common concordance across relationship groups is consistent with a genetic hypothesis, it can also be explained by common family environmental factors. There is a need for further pedigree studies, using twins and relatives, for example, and reliable information on the cumulative risk.