Statistical Approach to Genetic Epidemiology: Concepts and Applications [Kietas viršelis]

Foreword		vii
Preface		ix
Acknowledgments		xi
Molecular Genetics		1	(16)
Genetic information		2	(5)
Location of genetic information		2	(3)
Interpretation of genetic information		5	(1)
Translation of genetic information		5	(2)
Transmission of genetic information		7	(3)
Variations in genetic information		10	(5)
Individual differences in genetic information		10	(1)
Detection of variations		11	(4)
Problems		15	(2)
Formal Genetics		17	(26)
Mendel and his laws		18	(1)
Segregation patterns		19	(5)
Autosomal dominant inheritance		20	(1)
Autosomal recessive inheritance		21	(1)
X-chromosomal dominant inheritance		22	(1)
X-chromosomal recessive inheritance		23	(1)
Y-chromosomal inheritance		24	(1)
Complications ofMendelian segregation		24	(10)
Variable penetrance and expression		25	(2)
Age-dependent penetrance		27	(2)
Imprinting		29	(2)
Phenotypic and genotypic heterogeneity		31	(1)
Complex diseases		32	(2)
Hardy-Weinberg law		34	(5)
Problems		39	(4)
Genetic Markers		43	(12)
Properties of genetic markers		43	(5)
Types of genetic markers		48	(4)
Short tandem repeats (STRs)		48	(2)
Single nucleotide polymorphisms (SNPs)		50	(2)
Problems		52	(3)
Data Quality		55	(20)
Pedigree errors		55	(1)
Genotyping errors in pedigrees		56	(7)
Frequency of genotyping errors		57	(1)
Reasons for genotyping errors		58	(1)
Mendel checks		59	(2)
Checks for double recombinants		61	(2)
Genotyping errors in population-based studies		63	(9)
Causes of deviations from Hardy-Weinberg equilibrium		63	(1)
Tests for deviation from Hardy-Weinberg equilibrium for SNPs		64	(3)
Tests for deviation from Hardy-Weinberg equilibrium for STRs		67	(2)
Tests for compatibility with Hardy-Weinberg for SNPs		69	(3)
Problems		72	(3)
Genetic Map Distances		75	(14)
Physical distance		75	(1)
Map distance		76	(4)
Distance		76	(1)
Specific map functions		77	(1)
Correspondence between physical distance and map distance		78	(1)
Multilocus feasibility		79	(1)
Radiation hybrid distance		80	(1)
Linkage disequilibrium distance		81	(5)
Problems		86	(3)
Model-based Linkage Analysis		89	(32)
Linkage analysis between two genetic markers		90	(11)
Linkage analysis in phase-known pedigrees		90	(4)
Linkage analysis in phase-unknown pedigrees		94	(1)
Linkage analysis in pedigrees with missing genotypes		95	(6)
Linkage analysis between a genetic marker and a disease		101	(11)
Linkage analysis between a genetic marker and a disease in phase-known pedigrees		101	(4)
Linkage analysis between a genetic marker and a disease in general cases		105	(5)
Gain in information by genotyping additional individuals; power calculations		110	(2)
Significance levels in linkage analysis		112	(4)
Problems		116	(5)
Model-free Linkage Analysis		121	(34)
The principle of similarity		122	(2)
Mathematical foundation of affected sib-pair analysis		124	(1)
Common tests for affected sib-pair analysis		125	(12)
The maximum LOD score and the triangle test		126	(5)
Score- and Wald-type one-degree-of-freedom tests		131	(5)
Affected sib-pair tests using alleles shared identical by state		136	(1)
Properties of affected sib-pair tests		137	(2)
Sample size and power calculations for affected sib-pair studies		139	(7)
Recurrence risk ratios		139	(3)
Relationship between recurrence risk ratios and IBD probabilities		142	(2)
Sample size and power calculations for the mean test using recurrence risk ratios		144	(2)
Extensions to multiple marker loci		146	(2)
Extension to large sibships		148	(1)
Extension to large pedigrees		149	(1)
Extensions of the affected sib-pair approach		150	(3)
Covariates in affected sib-pair analyses		151	(1)
Multiple disease loci in affected sib-pair analyses		151	(1)
Estimating the position of the disease locus in affected sib-pair analyses		151	(1)
Typing unaffected relatives in sib-pair analyses		152	(1)
Problems		153	(2)
Quantitative Traits		155	(32)
Quantitative versus qualitative traits		156	(1)
The Haseman-Elston method		157	(10)
The simple Falconer model		159	(2)
The expected squared phenotypic difference at the trait locus		161	(2)
The expected squared phenotypic difference at the marker locus		163	(4)
Extensions of the Haseman-Elston method		167	(10)
Double squared trait difference		167	(1)
Extension to large sibships		168	(1)
Haseman-Elston revisited and the new Haseman-Elston method		169	(4)
Power and sample size calculations		173	(3)
Further extensions of the Haseman-Elston method		176	(1)
Variance component models		177	(4)
The univariate variance component model		177	(1)
The multivariate variance component model		178	(3)
Random sib-pairs, extreme probands and extreme sib-pairs		181	(6)
Empirical determination ofp-values		184	(1)
Problems		185	(2)
Fundamental Concepts of Association Analyses		187	(12)
Introduction to association		187	(3)
Principles of association		187	(2)
Study designs for association		189	(1)
Linkage disequilibrium		190	(7)
Measures for linkage disequilibrium		190	(4)
Extent of linkage disequilibrium		194	(3)
Problems		197	(2)
Association Analysis in Unrelated Individuals		199	(16)
Selection of cases and controls		200	(1)
Tests and estimates		200	(5)
Sample size calculation		205	(3)
Population stratification		208	(5)
Testing for population stratification		210	(1)
Structured association		211	(1)
Genomic control		212	(1)
Comparison of structured association and genomic control		213	(1)
Problems		213	(2)
Family-based Association Analysis		215	(28)
Haplotype relative risk		216	(1)
Transmission disequilibrium test (TDT)		217	(4)
Risk estimates for trio data		221	(2)
Sample size and power calculations for the TDT		223	(1)
Alternative test statistics		224	(1)
TDT for multiallelic markers		225	(3)
Test of single alleles		226	(1)
Global test statistics		226	(2)
TDT type tests for different family structures		228	(11)
TDT type tests for missing parental data		229	(2)
TDT type tests for sibship data		231	(5)
TDT type tests for extended pedigrees		236	(3)
Association analysis for quantitative traits		239	(2)
Problems		241	(2)
Haplotypes in Association Analyses		243	(20)
Reasons for studying haplotypes		244	(1)
Inference of haplotypes		245	(5)
Algorithms for haplotype assignment		245	(2)
Algorithms for estimating haplotype probabilities		247	(3)
Association tests using haplotypes		250	(2)
Haplotype blocks and tagging SNPs		252	(9)
Selection of markers by haplotypes		254	(3)
Selection of markers by linkage disequilibrium		257	(2)
Evaluation of marker selection approaches		259	(2)
Problems		261	(2)
Appendix A Algorithms Used in Linkage Analyses		263	(14)
A.1 The Lander-Green algorithm		263	(11)
A.1.1 The inheritance vector at a single genetic marker		264	(4)
A.1.2 The inheritance distribution given all genetic markers		268	(6)
A.2 The Cardon-Fulker algorithm		274	(2)
A.3 Problems		276	(1)
Solutions		277	(28)
References		305	(24)
Index		329

After studying statistics and mathematics at the University of Munich and obtaining his doctoral degree from the University of Dortmund, Andreas Ziegler received the Johann-Peter-S?h-Medal of the German Association for Medical Informatics, Biometry and Epidemiology for his post-doctoral work on "Model Free Linkage Analysis of Quantitative Traits" in 1999. In 2004, he was one of the recipients of the Fritz-Linder-Forum-Award from the German Association for Surgery. Andreas Ziegler is head of the Institute for Medical Biometry and Statistics at the University Clinic Schleswig-Holstein an acknowledged center of excellence for genetic epidemiological methods. Currently he is President of the German Region of the International Biometric Society. Inke R. Koenig studied psychology at the universities of Marburg (Germany) as a scholar of the German National Academic Foundation and Dundee (Scotland) with a grant from the German Academic Exchange Service (DAAD). She has done research work at the Institute of Medical Biometry and Epidemiology in Marburg and since 2001 at the Institute of Medical Biometry and Statistics in L? In 2004, she became vice director of the latter and also received the Fritz-Linder-Forum-Award from the German Association for Surgery. Besides holding the certificate for Biometrics in Medicine, she has collected teaching experience since 1998 as a lecturer for biomathematics, behavioural genetics, clinical epidemiology, genetic epidemiology, and evidence-based medicine.