Abstract
In addition to characterizing the distribution of genetic features of populations (mutation and allele frequencies; measures of Hardy–Weinberg equilibrium), genetic epidemiology and statistical genetics aim to explore and define the role of genomic variation in risk of disease or variation in traits of interest. To facilitate this kind of exploration, genetic epidemiology and statistical genetics address a series of questions:
-
1.
Does the disease tend to cluster in families more than expected by chance alone?
-
2.
Does the disease appear to follow a particular genetic model of transmission in families?
-
3.
Does variation at a particular genomic position tend to cosegregate with disease in families?
-
4.
Do specific genetic variants tend to be carried more frequently by those with disease than by those without these variants in a given population (or across families)?
The first question can be examined using studies of familial aggregation or correlation. An ancillary question: “how much of the susceptibility to disease (or variation in disease-related traits) might be accounted for by genetic factors?” is typically answered by estimating heritability, the proportion of variance in a trait or in risk to a disease attributable to genetics. The second question can be formally tested using pedigrees for which disease affection status or trait values are available through a modeling approach known as segregation analysis. The third question can be answered with data on genomic markers in pedigrees with affected members informative for linkage, where meiotic cross-over events are estimated or assessed. The fourth question is answerable using genotype data on genomic markers on unrelated affected and unaffected individuals and/or families with affected members and unaffected members. All of these questions can also be explored for quantitative (or continuously distributed) traits by examining variation in trait values between family members or between unrelated individuals. While each of these questions and the analytical approaches for answering them is explored extensively in subsequent chapters (heritability in Chapters 8 and 9; segregation in Chapter 12; linkage in Chapters 13–17; and association in Chapters 18–20), this chapter focuses on statistical methods to address questions of familial aggregation of qualitative phenotypes (e.g., disease status) or quantitative phenotypes.
While studies exploring genotype–phenotype correlations are arguably the most important and common type of statistical genetic study performed, these studies are performed under the assumption that genetic contributors at least partially explain risk of a disease or a trait of interest. This may not always be the case, especially with diseases or traits known to be strongly influenced by environmental factors. For this reason, before any of the last three questions described above can be answered, it is important to ask first whether the disease clusters among family members more than unrelated persons, as this constitutes evidence of a possible heritable contribution to disease, justifying the pursuit of studies answering the other questions. In this chapter, the underlying principles of familial aggregation studies are addressed to provide an understanding and set of analytical tools to help answer the question if diseases or traits of interest are likely to be heritable and therefore justify subsequent statistical genetic studies to identify specific genetic causes.
Similar content being viewed by others
References
Khoury MJ, Beaty TH, Cohen BH (1993) Fundamentals of genetic epidemiology. In: Monographs in epidemiology and biostatics, vol v. 19. Oxford University Press, New York
Tokuhata GK, Lilienfeld AM (1963) Familial aggregation of lung cancer in humans. J Natl Cancer Inst 30:289–312
Feinleib M, Garrison RJ, Fabsitz R, Christian JC, Hrubec Z, Borhani NO, Kannel WB, Rosenman R, Schwartz JT, Wagner JO (1977) The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results. Am J Epidemiol 106(4):284–285
Cohen BH (1980) Chronic obstructive pulmonary disease: a challenge in genetic epidemiology. Am J Epidemiol 112(2):274–288
Khoury MJ, Erickson JD, James LM (1982) Etiologic heterogeneity of neural tube defects: clues from epidemiology. Am J Epidemiol 115(4):538–548
Khoury MJ, Erickson JD, James LM (1982) Etiologic heterogeneity of neural tube defects. II. Clues from family studies. Am J Hum Genet 34(6):980–987
ten Kate LP, Boman H, Daiger SP, Motulsky AG (1982) Familial aggregation of coronary heart disease and its relation to known genetic risk factors. Am J Cardiol 50(5):945–953. doi:0002-9149(82)90400-3 [pii]
del Junco D, Luthra HS, Annegers JF, Worthington JW, Kurland LT (1984) The familial aggregation of rheumatoid arthritis and its relationship to the HLA-DR4 association. Am J Epidemiol 119(5):813–829
Sattin RW, Rubin GL, Webster LA, Huezo CM, Wingo PA, Ory HW, Layde PM (1985) Family history and the risk of breast cancer. JAMA 253(13):1908–1913
Nielsen HE, Haase P, Blaabjerg J, Stryhn H, Hilden J (1987) Risk factors and sib correlation in physiological neonatal jaundice. Acta Paediatr Scand 76(3):504–511
Beaty TH, Yang P, Munoz A, Khoury MJ (1988) Effect of maternal and infant covariates on sibship correlation in birth weight. Genet Epidemiol 5(4):241–253. doi:10.1002/gepi.1370050406
Maestri NE, Beaty TH, Liang KY, Boughman JA, Ferencz C (1988) Assessing familial aggregation of congenital cardiovascular malformations in case-control studies. Genet Epidemiol 5(5):343–354. doi:10.1002/gepi.1370050505
Linet MS, Van Natta ML, Brookmeyer R, Khoury MJ, McCaffrey LD, Humphrey RL, Szklo M (1989) Familial cancer history and chronic lymphocytic leukemia. A case-control study. Am J Epidemiol 130(4):655–664
Ponz de Leon M, Sassatelli R, Sacchetti C, Zanghieri G, Scalmati A, Roncucci L (1989) Familial aggregation of tumors in the three-year experience of a population-based colorectal cancer registry. Cancer Res 49(15):4344–4348
Redline S, Tosteson T, Tishler PV, Carskadon MA, Millman RP (1992) Studies in the genetics of obstructive sleep apnea. Familial aggregation of symptoms associated with sleep-related breathing disturbances. Am Rev Respir Dis 145(2 Pt 1):440–444. doi:10.1164/ajrccm/145.2_Pt_1.440
Lin JP, Cash JM, Doyle SZ, Peden S, Kanik K, Amos CI, Bale SJ, Wilder RL (1998) Familial clustering of rheumatoid arthritis with other autoimmune diseases. Hum Genet 103(4):475–482
Nestadt G, Samuels J, Riddle M, Bienvenu OJ 3rd, Liang KY, LaBuda M, Walkup J, Grados M, Hoehn-Saric R (2000) A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 57(4):358–363
Naldi L, Peli L, Parazzini F, Carrel CF (2001) Family history of psoriasis, stressful life events, and recent infectious disease are risk factors for a first episode of acute guttate psoriasis: results of a case-control study. J Am Acad Dermatol 44(3):433–438. doi:10.1067/mjd.2001.110876. S0190-9622(01)37292-4 [pii]
Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M, Moser KL, Begovich AB, Carlton VE, Li W, Lee AT, Ortmann W, Behrens TW, Gregersen PK (2005) Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 76(4):561–571. doi:10.1086/429096. S0002-9297(07)62868-7 [pii]
Beaty TH, Hetmanski JB, Fallin MD, Park JW, Sull JW, McIntosh I, Liang KY, Vanderkolk CA, Redett RJ, Boyadjiev SA, Jabs EW, Chong SS, Cheah FS, Wu-Chou YH, Chen PK, Chiu YF, Yeow V, Ng IS, Cheng J, Huang S, Ye X, Wang H, Ingersoll R, Scott AF (2006) Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations. Hum Genet 120(4):501–518. doi:10.1007/s00439-006-0235-9
Peretz I, Cummings S, Dube MP (2007) The genetics of congenital amusia (tone deafness): a family-aggregation study. Am J Hum Genet 81(3):582–588. doi:10.1086/521337. S0002-9297(07)61354-8 [pii]
Raynor LA, Pankow JS, Miller MB, Huang GH, Dalton D, Klein R, Klein BE, Cruickshanks KJ (2009) Familial aggregation of age-related hearing loss in an epidemiological study of older adults. Am J Audiol 18(2):114–118. doi:10.1044/1059-0889(2009/08-0035). 1059-0889_2009_08-0035 [pii]
Joossens M, Van Steen K, Branche J, Sendid B, Rutgeerts P, Vasseur F, Poulain D, Broly F, Colombel JF, Vermeire S, Chamaillard M (2010) Familial aggregation and antimicrobial response dose-dependently affect the risk for Crohn's disease. Inflamm Bowel Dis 16(1):58–67. doi:10.1002/ibd.20985
Whitehouse AJ (2010) Is there a sex ratio difference in the familial aggregation of specific language impairment? A meta-analysis. J Speech Lang Hear Res 53(4):1015–1025. doi:10.1044/1092-4388(2009/09-0078
Krogh C, Fischer TK, Skotte L, Biggar RJ, Oyen N, Skytthe A, Goertz S, Christensen K, Wohlfahrt J, Melbye M (2010) Familial aggregation and heritability of pyloric stenosis. JAMA 303(23):2393–2399. doi:10.1001/jama.2010.784. 303/23/2393 [pii]
Xiong L, Montplaisir J, Desautels A, Barhdadi A, Turecki G, Levchenko A, Thibodeau P, Dube MP, Gaspar C, Rouleau GA (2010) Family study of restless legs syndrome in Quebec, Canada: clinical characterization of 671 familial cases. Arch Neurol 67(5):617–622. doi:10.1001/archneurol.2010.67. 67/5/617 [pii
Saito YA, Petersen GM, Larson JJ, Atkinson EJ, Fridley BL, de Andrade M, Locke GR 3rd, Zimmerman JM, Almazar-Elder AE, Talley NJ (2010) Familial aggregation of irritable bowel syndrome: a family case-control study. Am J Gastroenterol 105(4):833–841. doi:10.1038/ajg.2010.116. ajg2010116 [pii]
Lichtenstein P, Carlstrom E, Rastam M, Gillberg C, Anckarsater H (2010) The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry 167(11):1357–1363. doi:10.1176/appi.ajp.2010.10020223. appi.ajp.2010.10020223 [pii]
Petersen L, Andersen PK, Sorensen TI (2010) Genetic influences on incidence and case-fatality of infectious disease. PLoS One 5(5):e10603. doi:10.1371/journal.pone.0010603
Yang YQ, Zhang XL, Wang XH, Tan HW, Shi HF, Fang WY, Liu X (2010) Familial aggregation of lone atrial fibrillation in the Chinese population. Intern Med 49(22):2385–2391
Royer RH, Koshiol J, Giambarresi TR, Vasquez LG, Pfeiffer RM, McMaster ML (2010) Differential characteristics of Waldenstrom macroglobulinemia according to patterns of familial aggregation. Blood 115(22):4464–4471. doi:10.1182/blood-2009-10-247973
Pinho T, Maciel P, Lemos C, Sousa A (2010) Familial aggregation of maxillary lateral incisor agenesis. J Dent Res 89(6):621–625. doi:10.1177/0022034510364486
Sweet RA, Bennett DA, Graff-Radford NR, Mayeux R, National Institute on Aging Late-Onset Alzheimer's Disease Family Study, G (2010) Assessment and familial aggregation of psychosis in Alzheimer's disease from the national institute on aging late onset Alzheimer's disease family study. Brain 133(Pt 4):1155–1162. doi:10.1093/brain/awq001
Scheurer ME, Etzel CJ, Liu M, Barnholtz-Sloan J, Wiklund F, Tavelin B, Wrensch MR, Melin BS, Bondy ML, Consortium G (2010) Familial aggregation of glioma: a pooled analysis. Am J Epidemiol 172(10):1099–1107. doi:10.1093/aje/kwq261
Kicinski M, Vangronsveld J, Nawrot TS (2011) An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PLoS One 6(10):e27130. doi:10.1371/journal.pone.0027130
Zhang Y, Cantor RM, MacGibbon K, Romero R, Goodwin TM, Mullin PM, Fejzo MS (2011) Familial aggregation of hyperemesis gravidarum. Am J Obstet Gynecol 204(3):230 e231–230 e237. doi:10.1016/j.ajog.2010.09.018
Niewold TB, Wu SC, Smith M, Morgan GA, Pachman LM (2011) Familial aggregation of autoimmune disease in juvenile dermatomyositis. Pediatrics 127(5):e1239–e1246. doi:10.1542/peds.2010-3022
Nervi A, Reitz C, Tang MX, Santana V, Piriz A, Reyes D, Lantigua R, Medrano M, Jimenez-Velazquez IZ, Lee JH, Mayeux R (2011) Familial aggregation of dementia with Lewy bodies. Arch Neurol 68(1):90–93. doi:10.1001/archneurol.2010.319
Goes FS, McCusker MG, Bienvenu OJ, Mackinnon DF, Mondimore FM, Schweizer B, Depaulo JR, Potash JB, National Institute of Mental Health Genetics Initiative Bipolar Disorder, C (2012) Co-morbid anxiety disorders in bipolar disorder and major depression: familial aggregation and clinical characteristics of co-morbid panic disorder, social phobia, specific phobia and obsessive-compulsive disorder. Psychol Med 42(7):1449–1459. doi:10.1017/S0033291711002637
de Klerk N, Alfonso H, Olsen N, Reid A, Sleith J, Palmer L, Berry G, Musk AB (2013) Familial aggregation of malignant mesothelioma in former workers and residents of Wittenoom, Western Australia. Int J Cancer 132(6):1423–1428. doi:10.1002/ijc.27758
Strate LL, Erichsen R, Baron JA, Mortensen J, Pedersen JK, Riis AH, Christensen K, Sorensen HT (2013) Heritability and familial aggregation of diverticular disease: a population-based study of twins and siblings. Gastroenterology 144(4):736–742 e731. doi:10.1053/j.gastro.2012.12.030. quiz e714
Harvey CJ, Gehrman P, Espie CA (2014) Who is predisposed to insomnia: a review of familial aggregation, stress-reactivity, personality and coping style. Sleep Med Rev 18(3):237–247. doi:10.1016/j.smrv.2013.11.004
Merikangas KR, Cui L, Heaton L, Nakamura E, Roca C, Ding J, Qin H, Guo W, Shugart YY, Zarate C, Angst J (2014) Independence of familial transmission of mania and depression: results of the NIMH family study of affective spectrum disorders. Mol Psychiatry 19(2):214–219. doi:10.1038/mp.2013.116
Kuo CF, Grainge MJ, See LC, Yu KH, Luo SF, Valdes AM, Zhang W, Doherty M (2015) Familial aggregation of gout and relative genetic and environmental contributions: a nationwide population study in Taiwan. Ann Rheum Dis 74(2):369–374. doi:10.1136/annrheumdis-2013-204067
Kuo CF, Grainge MJ, Valdes AM, See LC, Luo SF, Yu KH, Zhang W, Doherty M (2015) Familial aggregation of systemic lupus erythematosus and coaggregation of autoimmune diseases in affected families. JAMA Intern Med 175(9):1518–1526. doi:10.1001/jamainternmed.2015.3528
Jarrin DC, Rochefort A, Ivers H, Mérette C, Dauvilliers YA, Savard J, LeBlanc M, Morin CM (2017) Familial aggregation of insomnia. Sleep 40(2):zsw053. https://doi.org/10.1093/sleep/zsw053
Rice TK (2008) Familial resemblance and heritability. Adv Genet 60:35–49. doi:10.1016/S0065-2660(07)00402-6. S0065-2660(07)00402-6 [pii]
Visscher PM, Hill WG, Wray NR (2008) Heritability in the genomics era–concepts and misconceptions. Nat Rev Genet 9(4):255–266. doi:10.1038/nrg2322. nrg2322 [pii]
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748
Hopper JL, Hannah MC, Mathews JD (1984) Genetic analysis workshop II: pedigree analysis of a binary trait without assuming an underlying liability. Genet Epidemiol 1(2):183–188. doi:10.1002/gepi.1370010212
Connolly MA, Liang KY (1988) Conditional logistic regression models for correlated binary data. Biometrika 75(3):501–506. doi:10.1093/biomet/75.3.501
Hopper JL, Derrick PL (1986) A log-linear model for binary pedigree data. Genet Epidemiol Suppl 1:73–82
Liang K-Y, Beaty TH (1991) Measuring familial aggregation by using odds-ratio regression models. Genet Epidemiol 8(6):361–370. doi:10.1002/gepi.1370080602
Bishop YMM, Fienberg SE, Holland PW (1975) Discrete multivariate analysis : theory and practice. MIT Press, Cambridge, Mass
Liang KY, Beaty TH (2000) Statistical designs for familial aggregation. Stat Methods Med Res 9(6):543–562
Schwartz AG, Boehnke M, Moll PP (1988) Family risk index as a measure of familial heterogeneity of cancer risk. A population-based study in metropolitan Detroit. Am J Epidemiol 128(3):524–535
Breslow NE, Day NE(1980) Statistical methods in cancer research. IARC scientific publications, vol. no 32, <79, 82, 128>. International Agency for Research on Cancer, Lyon
Beaty TH, Maestri NE, Hetmanski JB, Wyszynski DF, Vanderkolk CA, Simpson JC, McIntosh I, Smith EA, Zeiger JS, Raymond GV, Panny SR, Tifft CJ, Lewanda AF, Cristion CA, Wulfsberg EA (1997) Testing for interaction between maternal smoking and TGFA genotype among oral cleft cases born in Maryland 1992–1996. Cleft Palate Craniofac J 34(5):447–454
Seibold MA, Schwartz DA (2010) The lung: the natural boundary between nature and nurture. Annu Rev Physiol 73:457–478. doi:10.1146/annurev-physiol-012110-142212
Garantziotis S, Schwartz DA (2010) Ecogenomics of respiratory diseases of public health significance. Annu Rev Public Health 31:37–51. doi:10.1146/annurev.publhealth.012809.103633. 31 p following 51
Demeo DL, Sandhaus RA, Barker AF, Brantly ML, Eden E, McElvaney NG, Rennard S, Burchard E, Stocks JM, Stoller JK, Strange C, Turino GM, Campbell EJ, Silverman EK (2007) Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency. Thorax 62(9):806–813. doi:10.1136/thx.2006.075846. thx.2006.075846 [pii]
Pare G, Cook NR, Ridker PM, Chasman DI (2010) On the use of variance per genotype as a tool to identify quantitative trait interaction effects: a report from the Women's genome health study. PLoS Genet 6(6):e1000981. doi:10.1371/journal.pgen.1000981
Murcray CE, Lewinger JP, Gauderman WJ (2009) Gene-environment interaction in genome-wide association studies. Am J Epidemiol 169(2):219–226. doi:10.1093/aje/kwn353. kwn353 [pii]
Hwang SJ, Beaty TH, Liang KY, Coresh J, Khoury MJ (1994) Minimum sample size estimation to detect gene-environment interaction in case-control designs. Am J Epidemiol 140(11):1029–1037
Foppa I, Spiegelman D (1997) Power and sample size calculations for case-control studies of gene-environment interactions with a polytomous exposure variable. Am J Epidemiol 146(7):596–604
Garcia-Closas M, Lubin JH (1999) Power and sample size calculations in case-control studies of gene-environment interactions: comments on different approaches. Am J Epidemiol 149(8):689–692
Sturmer T, Brenner H (2000) Potential gain in efficiency and power to detect gene-environment interactions by matching in case-control studies. Genet Epidemiol 18(1):63–80. doi:10.1002/(SICI)1098-2272(200001)18:1<63::AID-GEPI5>3.0.CO;2-O. [pii] 10.1002/(SICI)1098-2272(200001)18:1<63::AID-GEPI5>3.0.CO;2-O
Gauderman WJ (2002) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155(5):478–484
Claus EB, Risch NJ, Thompson WD (1990) Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol 131(6):961–972
Mettlin C, Croghan I, Natarajan N, Lane W (1990) The association of age and familial risk in a case-control study of breast cancer. Am J Epidemiol 131(6):973–983
Pulver AE, Liang KY (1991) Estimating effects of proband characteristics on familial risk: II. The association between age at onset and familial risk in the Maryland schizophrenia sample. Genet Epidemiol 8(5):339–350. doi:10.1002/gepi.1370080506
Liang K-Y, Zeger SL (1986) Longitudinal data analysis using generalized linear models. Biometrika 73(1):13–22. doi:10.1093/biomet/73.1.13
Liang KY (1987) Extended Mantel-Haenszel estimating procedure for multivariate logistic regression models. Biometrics 43(2):289–299
Liang KY, Pulver AE (1996) Analysis of case-control/family sampling design. Genet Epidemiol 13(3):253–270. doi:10.1002/(SICI)1098-2272(1996)13:3<253::AID-GEPI3>3.0.CO;2-7. [pii] 10.1002/(SICI)1098-2272(1996)13:3<253::AID-GEPI3>3.0.CO;2-7
Hsu L, Zhao LP (1996) Assessing familial aggregation of age at onset, by using estimating equations, with application to breast cancer. Am J Hum Genet 58(5):1057–1071
Li H, Yang P, Schwartz AG (1998) Analysis of age of onset data from case-control family studies. Biometrics 54(3):1030–1039
Liang KY (1991) Estimating effects of probands' characteristics on familial risk: I. Adjustment for censoring and correlated ages at onset. Genet Epidemiol 8(5):329–338. doi:10.1002/gepi.1370080505
Liang KY, Zeger SL (1993) Regression analysis for correlated data. Annu Rev Public Health 14:43–68. doi:10.1146/annurev.pu.14.050193.000355
Khoury MJ, Beaty TH, Liang KY (1988) Can familial aggregation of disease be explained by familial aggregation of environmental risk factors? Am J Epidemiol 127(3):674–683
Thomas DC (2004) Statistical methods in genetic epidemiology. Oxford University Press, Oxford; New York
Bratt O, Garmo H, Adolfsson J, Bill-Axelson A, Holmberg L, Lambe M, Stattin P (2010) Effects of prostate-specific antigen testing on familial prostate cancer risk estimates. J Natl Cancer Inst 102(17):1336–1343. doi:10.1093/jnci/djq265. djq265 [pii]
Liu JZ, Erlich Y, Pickrell JK (2017) Case-control association mapping by proxy using family history of disease. Nat Genet 49(3):325–331. doi:10.1038/ng.3766
Hayes BJ, Bowman PJ, Chamberlain AJ, Goddard ME (2009) Invited review: genomic selection in dairy cattle: progress and challenges. J Dairy Sci 92(2):433–443. doi:10.3168/jds.2008-1646
Garrick DJ, Taylor JF, Fernando RL (2009) Deregressing estimated breeding values and weighting information for genomic regression analyses. Genet Sel Evol 41:55. doi:10.1186/1297-9686-41-55
Cole JB, VanRaden PM, O'Connell JR, Van Tassell CP, Sonstegard TS, Schnabel RD, Taylor JF, Wiggans GR (2009) Distribution and location of genetic effects for dairy traits. J Dairy Sci 92(6):2931–2946. doi:10.3168/jds.2008-1762
Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR (2003) Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 290(15):2030–2040. doi:10.1001/jama.290.15.2030
Joshi PK, Fischer K, Schraut KE, Campbell H, Esko T, Wilson JF (2016) Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan. Nat Commun 7:11174. doi:10.1038/ncomms11174
Pilling LC, Atkins JL, Bowman K, Jones SE, Tyrrell J, Beaumont RN, Ruth KS, Tuke MA, Yaghootkar H, Wood AR, Freathy RM, Murray A, Weedon MN, Xue L, Lunetta K, Murabito JM, Harries LW, Robine JM, Brayne C, Kuchel GA, Ferrucci L, Frayling TM, Melzer D (2016) Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants. Aging 8(3):547–560. doi:10.18632/aging.100930
Tan Q, Zhao JH, Li S, Kruse TA, Christensen K (2010) Power assessment for genetic association study of human longevity using offspring of long-lived subjects. Eur J Epidemiol 25(7):501–506. doi:10.1007/s10654-010-9465-1
Beaty TH, Skjaerven R, Breazeale DR, Liang KY (1997) Analyzing sibship correlations in birth weight using large sibships from Norway. Genet Epidemiol 14(4):423–433. doi:10.1002/(SICI)1098-2272(1997)14:4<423::AID-GEPI7>3.0.CO;2-3. [pii] 10.1002/(SICI)1098-2272(1997)14:4<423::AID-GEPI7>3.0.CO;2-3
Wedderburn RWM (1974) Quasi-likelihood functions, generalized linear models, and the Gauss-Newton method. Biometrika 61(3):439–447. doi:10.1093/biomet/61.3.439
Hanrahan LP, Mirkin I, Olson J, Anderson HA, Fiore BJ (1990) SMRFIT: a statistical analysis system (SAS) program for standardized mortality ratio analyses and Poisson regression model fits in community disease cluster investigations. Am J Epidemiol 132(1 Suppl):S116–S122
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media LLC
About this protocol
Cite this protocol
Naj, A.C., Beaty, T.H. (2017). Detecting Familial Aggregation. In: Elston, R. (eds) Statistical Human Genetics. Methods in Molecular Biology, vol 1666. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7274-6_8
Download citation
DOI: https://doi.org/10.1007/978-1-4939-7274-6_8
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-7273-9
Online ISBN: 978-1-4939-7274-6
eBook Packages: Springer Protocols