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EPIB 668 Examples of Familial Aggregation and Twin Studies

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EPIB 668 Examples of Familial Aggregation and Twin Studies EPIB 668 Examples of familial aggregation and twin studies Aur´elieLabbe - Winter 2011. 1 / 68 OUTLINE What is familial aggregation ? Case-control and cohort design: the family history approach Example 1: Familial aggregation of lung cancer Twin study design Example 2: Familial aggregation of cancer Heritability: definition The variance component model to compute heritability Twin studies to estimate heritability Example 3: Compulsive hoarding 2 / 68 WHAT IS FAMILIAL AGGREGATION ? 3 / 68 Genetic epidemiology questions 4 / 68 What is familial aggregation ? First step in pursuing a possible genetic etiology of the disease Based on phenotypic data only (don't need DNA) Demonstrate that the disease tends to run in families more than what would expect by chance Examine how that familial tendency is modified by the degree or type of relationship, age or environmental factors Important Familial aggregation does not separate genetic from environment 5 / 68 Rational of aggregation studies Identify a group of individuals with a specific disease and determine whether relatives have an excess frequency of the same disease when compared to an appropriate reference population Often, phenotype of interest is a disease (i.e. affected vs non-affected). But it can also be a physiological trait that has a continuous distribution (e.g cholesterol levels) 6 / 68 CASE-CONTROL AND COHORT DESIGN: THE FAMILY HISTORY APPROACH 7 / 68 Issues in designing family studies Goal is to demonstrate that the disease tends to run in families more than what would expect by chance Need to sample families rather than individuals In standard epi. studies, it is hard enough to find appropriate sampling frames for individuals ... this is even harder for families (in most countries, including US) ! For these reasons, most studies of familial aggregation of disease are based on ascertainment of probands (cases or controls), followed by identification of their family members. 8 / 68 Different types of designs Case-control or cohort approach: Can obtain information from the probands themselves concerning their family history (presence of disease in their relatives) Can enroll relatives in the study for a more detailed evaluation Usually easier to adapt the case-control design for family studies, rather than the cohort design Other designs: Twin studies Adoption studies 9 / 68 Familial aggregation based on Family History (FH) Positive FH = presence of disease in one or more first degree relatives FH should not be considered as a simple attribute of a person, comparable to age or cigarette smoking Depends on many factors: No of relatives and types of relatives Biologic relationship with the case/control Age distribution of relatives Disease frequency in the population 10 / 68 More on Family History... FH is in general obtained from the cases and controls themselves (or from spouses and parents, if not available). FH can be: Abbreviated: ask about the presence of disease in relatives Detailed: detailed inquiry about relatives of cases and controls with and without the disease. For example, one can extend the FH to a multilevel scale, such as: First degree, other relative, none Two or more, one, none Parent or sib under age 50, parent or sib over age 50, none Plenty of scope for imagination ! 11 / 68 The ideal Family History information... For whatever type of relatives to be considered, the ideal information would be: Number of relatives of each type at risk Their disease status (including specific diagnoses) Sexes Ages at risk (birth dates and dates of diagnosis or death Trade off between the number of relative types to be considered and the extend and quality of the information collected. 12 / 68 Example 1 Familial cancer history and lung cancer risk in United States nonsmoking men and women. 13 / 68 14 / 68 Example 1 Population based case-control study of lung cancer in non-smoking men and women in NY state from 1982 to 1984 In-person interviews completed for 437 lung cancer cases and 437 matched population controls (matched on sex, age, smoking history, county of residence and types of interview) Cases and controls reported their FH of cancer on parents, siblings and children Information collected on relatives: country of birth year of birth and death smoking status (yes/no) presence of cancer (yes/no), type of cancer and year of diagnosis 15 / 68 Example 1 Table 1 Sociodemographic characteristics of nonsmoking men and women with lung cancer, population controls, and case and control family members; New York Lung Cancer Study, 1982–1984 Cases Controls Sex Females 218 (49.9%) 218 (49.9%) Males 219 (50.1%) 219 (50.1%) Mean age (range) 67 (31–81) 68 (35–82) Smoking history Never 197 (45.1%) 197 (45.1%) Former 240 (54.9%) 240 (54.9%) Interview type Self 296 (67.7%) 305 (69.8%) Surrogate 141 (32.3%) 132 (30.2%) Mean years school (range) 11.5 (0–24) 12.7 (3–20) Histologic type Adenocarcinoma 222 (50.8%) Epidermoid/squamous 109 (24.9%) Other 106 (24.3%) Marital status Ever 374 (86.8%) 398 (91.7%) Never 57 (13.2%) 36 (8.3%) Mean age fathers 70 71 % Fathers who smoked 56 55 Mean age mothers 72 74 % Mothers who smoked 12 11 Mean age brothers 60 62 Mean No. of brothers (range) 1.82 (0–8) 1.49 (0–8) % Who smoked 62 58 Mean age sisters 62 65 Mean No. of sisters (range) 1.75 (0–6) 1.56 (0–7) % Who smoked 33 31 Mean age children 35 35 Mean No. of children (range) 1.93 (0–8) 2.08 (0–11) % Who smoked 42 38 16 / 68 Example 1: Lung cancer risk Table 2 Parental cancer history and risk of lung cancer in nonsmoking men and women; New York Lung Cancer Study, 1982–1984 No. of No. of a OR (95% CI) P cases controls Father Any cancer Yes 75 49 1.67 (1.12–2.48) 0.01 No 296 322 Lung cancer Yes 16 9 1.87 (0.79–4.42) 0.15 No 355 362 Aerodigestive tract cancer Yes 27 11 2.78 (1.30–5.95) 0.009 No 344 360 Digestive cancer Yes 25 21 1.20 (0.66–2.17) 0.55 No 346 350 Prostate cancer Yes 8 8 1.00 (0.38–2.66) 1.00 No 363 363 Mother Any cancer Yes 75 63 1.24 (0.85–1.80) 0.26 No 301 313 Lung cancer Yes 2 3 0.67 (0.11–3.99) 0.66 No 374 373 Aerodigestive tract cancer Yes 2 4 0.50 (0.09–2.73) 0.42 No 374 372 Digestive cancer Yes 27 22 1.28 (0.69–2.37) 0.44 No 349 354 Breast cancer Yes 25 13 2.00 (1.00–4.00) 0.049 No 351 363 17 / 68 Example 1: Lung cancer risk Cases were more likely than their matched controls to report a paternal history of any cancer and aerodigestive tract cancer Cases and controls reported a similar maternal history of cancer, with the exception of breast cancer, which reportedly occurred two times more frequently in mothers of cases than in mothers of matched controls 18 / 68 Example 1: Lung cancer risk Table 3 Cancer history in siblings and offspring and risk of lung cancer in nonsmoking men and women; New York Lung Cancer Study, 1982–1984 No. of No. of a OR (95% CI) P cases controls Sister Any cancer Yes 84 54 1.66 (1.11–2.47) 0.01 No 243 257 Lung cancer Yes 9 2 4.14 (0.88–19.46) 0.07 No 318 309 Aerodigestive tract cancer Yes 11 3 3.50 (0.96–12.74) 0.058 No 316 308 Digestive cancer Yes 18 11 1.70 (0.77–3.77) 0.19 No 309 300 Breast cancer Yes 24 11 2.07 (0.99–4.31) 0.053 No 303 300 19 / 68 Example 1: Lung cancer risk Cases were significantly more likely than their matched controls to report having had sisters with any cancer Cases were significantly more likely than controls to report having had brothers with any cancer 20 / 68 Example 1: Cohort analysis Cohort of fathers, mothers, sisters and brothers were constructed Variable included were age and smoking status of the cohort member Indicator variable was included to indicate if the relative was related to a case or a control Logistic models were performed to predict the occurrence of various cancers in the cohort of interest. Compute Risk Ratios reflecting the risk of being a case relative as compared to a control relative, controlling for the relative's age and smoking status. 21 / 68 Example 1: Cohort analysis Table 4 Cohort analysis of parental cancer history and risk of lung cancer in nonsmoking men and women; New York Lung Cancer Study, 1982–1984 a RR (95% CI) P Father Any cancer Yes 1.90 (1.27–2.85) 0.002 No Lung cancer Yes 1.85 (0.80–4.33) 0.15 No Aerodigestive tract cancer Yes 2.77 (1.34–5.74) 0.0059 No Digestive cancer Yes 1.27 (0.69–2.34) 0.44 No Prostate cancer Yes 1.51 (0.52–4.42) 0.45 No 22 / 68 Example 1: Cohort analysis Fathers of cases were at greater risk of developing any cancer and aerodigestive tract cancers compared to fathers of controls. Mothers of cases were at greater risk of developing any cancer and breast cancer compared to mothers of controls. 23 / 68 TWIN STUDY DESIGN 24 / 68 Other type of design: twin studies Provide a simple way to separate genetic from environmental factors (in theory) Usually collect monozygotic (MZ) and dizygotic (DZ) twins: MZ share 100% of genes DZ share 50% of genes in average (as full sibs) By comparing MZ to DZ twins for concordance of disease, one can assess the relative importance of of genetic and environmental factors.
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