Approaches to handling incomplete data in family-based association testing

Data Interpretation, Statistical; Family; Female; Genetics, Medical/*statistics & numerical data; Genotype; Haplotypes; Humans; Male; Models, Statistical

Abstract :

[en] The high throughput of data arising from the complete sequence of the human genome has left statistical geneticists with a rich and extensive information source. The wide availability of software and the increase in computing power has improved the possibilities to access and process such data. One problem is incompleteness of the data: unobserved or partially observed data points due to technical reasons or reasons associated with the patient's status or erroneous measurements of phenotype or genotype, to name a few. When not properly accounted for, these sources of incompleteness may seriously jeopardize the credibility of results from analyses. In this paper we provide some perspectives on the occurrence and analysis of different forms of incomplete data in family-based genetic association testing.

Disciplines :

Genetics & genetic processes

Author, co-author :

Van Steen, Kristel ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique

Laird, N. M.

Markel, P.

Molenberghs, G.

Language :

English

Title :

Approaches to handling incomplete data in family-based association testing

Publication date :

2007

Journal title :

Annals of Human Genetics

ISSN :

0003-4800

eISSN :

1469-1809

Publisher :

Cambridge University Press, Cambridge, United Kingdom

Volume :

Issue :

Pt 2

Pages :

141-51

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

2006/11/14

Available on ORBi :

since 23 May 2010

Statistics

Number of views

30 (2 by ULiège)

Number of downloads

2 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Abecasis, G. R., Cherny, S. S. & Cardon, L. R. (2001) The impact of genotyping error on family-based analysis of quantitative traits. Eur J Hum Genet 9, 130-134.
Allen, A. S., Rathouz, P. J. & Satten, G. A. (2003) Informative missingness in genetic association studies: Case-parent designs. Am J Hum Genet 72, 671-680.
Barral, S., Haynes, C., Levenstien, M. A. & Gordon, D. (2005) Precision and type I error rate in the presence of genotype errors and missing parental data: A comparison between original TDT and TDTae statistics. BMC Genet 6, S150.
Bourgain, C., Genin, E., Quesneville, H. & Clerget-Darpoux, F. (2000) Search for multifactorial disease susceptibility genes in founder populations. Ann Hum Genet 64, 255-265.
Chang, Y. C., Kim, J. D., Schwander, K., Rao, D. C., Miller, M., Weder, A. B., Cooper, R. S., Schork, N. J., Province, M. A., Morrison, A. C., Kardia, S., Quertermous, T. & Chakravarti, A. (2006) The impact of data quality on the identification of complex disease genes: Experience from the Family Blood Pressure Program. Eur J Hum Genet 14, 469-477.
Chen, Y. H. (2004) New approach to association testing in case-parent designs under informative parental missingness. Genet Epidemiol 27, 131-140.
Clark, A. G. (1990) Inference of haplotypes from PCR-amplified samples of diploid populations. Mol Biol Evol 7, 111-122.
Clayton, D. (1999) A Generalization of the Transmission/Disequilibrium Test for Uncertain-Haplotype Transmission. Am J Hum Genet 65, 1170-1177.
Clayton, D. & Jones, H. (1999) Transmission/Disequilibrium Tests for Extended Marker Haplotypes. Am J Hum Genet 65, 1161-1169.
Cordell, H. & Clayton, D. (2002) A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: Application to HLA in type 1 diabetes. Am J Hum Genet 70, 124-141.
Curtis D. & Sham P. C. (1995). A note on the application of the transmission/disequilibrium test when a parent is missing. Am J Hum Genet 56, 811-812.
Dempster, A. P., Laird, N. M. & Rubin, D. B. (1977) Maximum likelihood from incomplete data via the EM algorithm (with discussion). J Roy Stat Soc B 39, 1-38.
Douglas, J. A., Boehnke, M., Gillanders, E., Trent, J. M. & Gruber, S. B. (2001) Experimentally-derived haplotypes substantially increase the efficiency of linkage disequilibrium studies. Nat Genet 28, 361-364.
Douglas, J. A., Skol, A. D. & Boehnke, M. (2002) Probability of detection of genotyping errors and mutations as inheritance inconsistencies in nuclear-family data. Am J Hum Genet 70, 487-495.
Ewens, W. J. & Spielman, R. S. (1995) The transmission/ disequilibrium test: History, subdivision, and admixture. Am J Hum Genet 57, 455-564.
Excoffier, L. & Slatkin, M. (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12, 921-927.
Falk, C. T. & Rubinstein, P. (1987) Haplotype relative risks: An easy reliable way to construct a proper control sample for risk calculations. Ann Hum Genet 51, 227-233.
Gauderman, W. J., Witte, J. S. & Thomas, D. C. (1999) Family-Based Association Studies. J Natl Cancer I Monographs No. 26, 31-37.
Geller, F. & Ziegler, A. (2002) Detection rates for genotyping errors in SNPs using the trio design. Hum Hered 54, 111-117.
Ghosh-Dastidar, B. & Schafer, J. L. (2003) Multiple edit/multiple imputation for continuous multivariate survey data. J Am Stat Assoc 98, x-x.
Glynn, R. J., Laird, N. M. & Rubin, D. B. (1986) Selection modeling versus mixture modeling with nonignorable nonresponse. In shape Drawing Inferences from Self-Selected Samples, Ed. H. Wainer, pp. 115-142. New York: Springer-Verlag.
Gordon, D., Haynes, C., Johnnidis, C., Patel, S. B., Bowcock, A. M. & Ott, J. (2004) A transmission disequilibrium test for general pedigrees that is robust to the presence of random genotyping errors and any number of untyped parents. Eur J Hum Genet 12, 752-761.
Gordon, D., Heath, S. C., Liu, X. & Ott, J. (2001) A transmission/ disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data. Am J Hum Genet 69, 371-380.
Gordon, D., Heath, S. C. & Ott, J. (1999) True pedigree errors more frequent than apparent errors for single nucleotide polymorphisms. Hum Hered 49, 65-70.
Gordon, D., Leal, S. M., Heath, S. C. & Ott, J. (2000) An analytic solution to single nucleotide polymorphism error-detection rates in nuclear families: Implications for study design. Pac Symp Biocomput 663-674.
Göring, H. H. H. & Terwilliger, J. D. (2000a) Linkage analysis in the presence of errors I: Complex-valued recombination fractions and complex phenotypes. Am J Hum Genet 66, 1095-1106.
Göring, H. H. H. & Terwilliger, J. D. (2000b) Linkage analysis in the presence of errors II: Marker-locus genotyping errors modeled with hypercomplex recombination fractions. Am J Hum Genet 66, 1107-1118.
Göring, H. H. H. & Terwilliger, J. D. (2000c) Linkage analysis in the presence of errors III: Marker-loci and their map as nuisance parameters. Am J Hum Genet 66, 1298-1309.
Göring, H. H. H. & Terwilliger, J. D. (2000d) Linkage analysis in the presence of errors IV: Joint pseudomarker analysis of linkage and/ or linkage disequilibrium on a mixture of pedigrees and singletons when the mode of inheritance cannot be accurately specified. Am J Hum Genet 66, 1310-1327.
Hawley, M. E. & Kidd, K. K. (1995) HAPLO: A program using the EM algorithm to estimate the frequencies of multi-site haplotypes. J Hered 86, 409-411.
Heitjan, D. F. & Rubin, D. B. (1991) Ignorability and coarse data. Ann. Stat. 19, 2244-2253.
Hirschhorn, J. N. & Daly, M. J. (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6, 95-108.
Horton, N. J. & Lipsitz, S. R. (2001) Multiple imputation in practice: Comparison of software packages for regression models with missing variables. Am Stat Assoc 35, 244-254.
Horvath, S. & Laird, N. M. (1998) A discordant-sibship test for disequilibrium and linkage: No need for parental data. Am J Hum Genet 63, 1886-1897.
Horvath, S., Xu, X. & Laird, N. M. (2001) The family based association test method: Strategies for studying general genotype-phenotype associations. Eur J Hum Genet 9, 301-306.
Horvath, S., Xin, X., Lake, S. L., Silverman, E. K., Weiss, S. T. & Laird, N. M. (2004) Family-based tests for associating haplotypes with general phenotype data: Application to asthma genetics. Genet Epi 26, 61-69.
Kenward, M. G., Goetghebeur, E. J. T. & Molenberghs, G. (2001) Sensitivity analysis of incomplete categorical data. Stat Model 1, 31-48.
Kuechenhoff, H. & Carroll, R. J. (1997) Segmented regression with errors in predictors: Semi-parametric and parametric methods. Stat Med 16, 169-188.
Laird, N. M., Horvath, S. & Xu, X. (2000) Implementing a unified approach to family-based tests of association. Genet Epi 19 (suppl 1), S36-S42.
Lange, C., DeMeo, D. L., Silverman, E., Weiss, S. & Laird, N. M. (2003a) Using the noninformative families in family-based association tests: A powerful new testing strategy. Am J Hum Genet 73, 801-811.
Lange, C., Lyon, H., DeMeo, D. L., Raby, B. A., Silverman, E. & Weiss, S. (2003b) A new powerful non-parametric two-stage approach for testing multiple phenotypes in family-based association studies. Hum Hered 56, 10-17.
Lange, C., Silverman, E. K., Xu, X., Weiss, S. T. & Laird, N. M. (2003c) A multivariate family-based association test using generalized estimating equations: FBAT-GEE. Biostatistics 4, 195-206.
Lee, W. C. (2002) Transmission/disequilibrium test when neither parent is available in some families: A non-iterative approach. J Cancer Epidemiol Prev 7, 97-103.
Little, R. J. A. & Rubin, D. B. (1987) Statistical Analysis with Missing Data. New York: John Wiley & Sons.
Little, R. J. A. (1993) Pattern-mixture models for multivariate incomplete data. J Am Stat Assoc 88, 125-134.
Little, R. J. A. (1995) Modeling the drop-out mechanism in repeated-measures studies. J Am Stat Assoc 90, 1112-1121.
Long, J. C., Williams, R. C. & Urbanek, M. (1995) An E-M algorithm and testing strategy for multiple-locus haplotypes. Am J Hum Genet 56, 799-810.
Lunetta, K. L., Faraone, S. V., Biederman, J. & Laird, N. M. (2000) Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions. Am J Hum Genet 66, 605-614.
Mallinckrodt, C. H., Scott Clark, W., Carroll, R. J. & Molenberghs G. (2003) Assessing response profiles from incomplete longitudinal clinical trial data with subject dropout under regulatory conditions. Journal of Biopharmaceutical Statistics 13, 179-190.
Martin, E. R., Monks, S. A., warren, L. L. & Kaplan, N. L. (2000) A test for linkage and association in general pedigrees: The pedigree disequilirium test. Am J Hum Genet 67, 146-154.
Mitchell, A. A., Cutler, D. J. & Chakravanti, A. (2003) Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test. Am J Hum Genet 72, 598-610.
Molenberghs, G., Goetghebeur, E. J. T., Lipsitz, S. R. & Kenward, M. G. (1999) Non-random missingness in categorical data: Strengths and limitations. The American Statistician 53, 110-118.
Molenberghs, G., Kenward, M. G. & Goetghebeur, E. (2001) Sensitivity analysis for incomplete contingency tables: The Slovenian plebiscite case. Appl Stat 50, 15-29.
Murhpy, A., Van Steen, K. & Lange, C. (2004) On missing phenotype data in multivariate family based association tests: FBAT-GEE-IMP and imputation strategies based on the EM-algorithm, the DA-algorithm and the conditional mean model. Far East Journal of Theoretical Statistics 13, 175-188.
Niu, T. (2004) Algorithms for inferring haplotypes. Genet Epi 27, 334-347.
Pearl, J. (2000) Causality: Models, reasoning, and inference. Publisher Cambridge University Press, New York, NY, USA.
Raab, G. M. & Donnelly, C. A. (1999) Information on sexual behaviour when some data are missing. Appl Statist 48, 117-133.
Rabinowitz D. & Laird, N. (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 50, 211-223.
Rice, J. P., Neuman, R. J., Hoshaw, S. L., Daw, E. W. & Gu, C. (1995) TDT with covariates and genomic screens with mod scores: Their behavior on simulated data. Genet Epi 12, 659-664.
Rubin, D. B. (1976) Inference and missing data. Biometrika 63, 581-592.
Rubin, D. B. (1977) Formalizing subjective notions about the effect of nonrespondents in sample surveys. J Am Stat Assoc 72, 538-543.
Rubin, D. B. (1987) Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons.
Schafer J. L. (1997) Analysis of Incomplete Multivariate Data. London: Chapman & Hall.
Schaid, D. J. (1996) General score tests for associations of genetic markers with disease using cased and their parents. Genet Epi 13, 423-449.
Schaid, D. J. & Sommer, S. S. (1993) Genotype relative risks: methods for design and analysis of candidate-gene association studies. Am J Hum Genet 53, 1114-1126.
Schaid, D. J. & Rowland, C. M. (1999) Quantitative trait transmission disequilibrium test: Allowance for missing parents. Genet Epi 17, Suppl, S307-S312.
Schaid, D. J., Rowland, C. M., Tines, D. E., Jacobson, R. M. & Poland, G. A. (2002) Score test for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70, 425-434.
Scharfstein, D. O., Rotnitzky, A. & Robins, J. M. (1999) Adjusting for non-ignorable drop-out using semiparametric nonresponde models (with discussion). J Am Stat Assoc 94, 1096-1146.
Self, S. G., Longton, G., Kopecky, K. J. & Liang, K-Y. (1991) On estimating HLA/disease association with application to a study of aplastic anemia. Biometrics 47, 53-61.
Seltman, H., Roeder, K. & Devlin, B. (2001) Transmission/ Disequilibrium Test Meets Measured Haplotype Analysis: Family-Based Association Analysis Guided by Evolution of Haplotypes. Am J Hum Genet 68, 1250-1263.
Sham, P. C. & Curtis, D. (1995) An extended transmission/ disequilibrium test (TDT) for multi-allele marker loci. Ann Hum Genet 59, 323-336.
Sobel, E., Papp, J. C. & Lange, K. (2002) Detection and integration of genotyping errors in statistical genetics. Am J Hum Genet 70, 496-508.
Spielman, R. S., Mc Ginnis, R. E. & Ewens, W. J. (1993) Transmission test for linkage disequilibrium: The insuline gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 65, 578-580.
Spielman, R. S., McGinnis, R. E. & Ewens, W. J. (1994) The transmission/disequilibrium test detects cosegregation and linkage. Am J Hum Genet 54, 559-60; author reply 560-563.
Spielman, R. S. & Ewens, W. J. (1998) A sibship test for linkage in the presence of association: The sib transmission/disequilibrium test. Am J Hum Genet 62, 450-458.
Stephens, M., Smith, N. J. & Donnelly, P. (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 69, 906-914.
Stephens, M. & Donnelly, P. (2003) A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73, 1162-1169.
Stephens, M. & Scheet, P. (2005) Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation; Am J Hum Genet 76, 449-462.
Sun, F., Flanders, W. D., Yang, Q. & Khoury, M. J. (1999). Transmission disequilibrium test (TDT) when only one parent is available: The 1-TDT. Am J Epidemiol 150, 97-104.
Tanner, M. A. & Wong, W. H. (1987) The calculation of posterior distributions by data augmentation. J Am Stat Assoc 82, 528-550.
Terwilliger, J. D. & Ott, J. (1994) Handbook of human genetic linkage. Johns Hopkins University Press, Baltimore.
Thijs, H., Molenberghs, G., Michiels, B., Verbeke, G. & Curran, D. (2001) Strategies to fit pattern-mixture models. Biostatistics 3, 245-265.
Thomson, G. (1995) Mapping disease genes: Family-based association studies. Am J Hum Genet 57, 487-498.
Vach, W. & Blettner, M. (1995) Logistic regression with incompletely observed categorical covariates - Investigating the sensitivity against violation of the missing at random assumption. Stat Med 14, 1315-1329.
van Dyck, D. A. & Meng, X-L. (2001) The art of data augmentation. Journal of Graphical and Computational Statistics 10, 1-111.
Van Steen, K. & Lange, C. (2005) PBAT: A comprehensive software package for genome-wide association analysis of complex family-based studies. Journal of Human Genomics 2, 1-3.
Van Steen, K., Mcqueen, M. B., Herbert, A., Raby, B., Lyon, H., Demeo, D. L., Murphy, A., Su, J., Datta, S., Rosenow, C., Christman, M., Silverman, E. K., Laird, N. M., Weiss, S. T. & Lange, C. (2005b), Screening and Replication in Family-Based Association Testing using the Same Data Set. Nature Genetics 37, 683-691.
Verbeke, G. & Molenberghs, G. (2000) Linear Mixed Models for Longitudinal Data. New York: Springer-Verlag.
Verbeke, G., Molenberghs, G., Thijs, H., Lesaffre, E. & Kenward, M. G. (2001) Sensitivity analysis for non-random dropout: A local influence approach. Biometrics 57, 43-50.
Weinberg, C. R. (1999) Allowing for missing parents in genetic studies of case-parent triads. Am J Hum Genet 64, 1186-1193.
Whittemore, A. S., Halpern, J. & Ahsan H. (2005) Covariate adjustment in family-based association studies. Genet Epi 28, 244-255.
Xie, F. & Paik, M. C. (1997) Multiple imputation methods for the missing covariates in generalized estimating equation. Biometrics 53, 1538-1546.
Zhang, S., Pakstis, A. J., Kidd, K. K. & Zhao, H. (2001) Comparisons of two methods for haplotype frequency estimation from population data. Am J Hum Genet 69, 906-912.
Zhao, H., Zhang, S., Merikangas, K., Trixler, M., Wildenauer, D., Sun, F. & Kidd, K. (2000) Transmission/Disequilibrium tests using multiple tightly linked markers. Am J Hum Genet 67, 939-946.