Using survival data in gene mapping : using survival data in genetic linkage and family-based association analysis Callegaro, A.

Using survival data in gene mapping : using survival data in genetic linkage and family-based association analysis

Callegaro, A.

Citation

Callegaro, A. (2010, June 17). Using survival data in gene mapping : using survival data in genetic linkage and family-based association analysis.

Retrieved from https://hdl.handle.net/1887/15696

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/15696

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Using survival data in gene mapping

Using survival data in genetic linkage and family-based association analysis

P

ter verkrijging van

de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof.mr. P.F. van der Heijden,

volgens besluit van het College voor Promoties te verdedigen op donderdag 17 Juni 2010

klokke 15.00 uur

door

Andrea Callegaro

geboren te Dolo (Italie) in 1974

P ROMOTIECOMMISSIE

PROMOTORES: Prof. dr. H. C. van Houwelingen Prof. dr. J. J. Houwing-Duistermaat

OVERIGE LEDEN: Prof. dr. P. Slagboom

·Moleculaire epidemiologie, LUMC Prof. dr. F. A. van Eeuwijk

·Biometris, Wageningen UR Prof. dr. L. Hsu

·Public Health Sciences Division,

Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A.

Contents

1 Introduction and overview 1

1.1 Frailty models . . . 1

1.2 Nonparametric linkage analysis . . . 3

1.3 Family based association analysis . . . 8

1.4 Outline of the thesis . . . 9

2 Score test for age at onset genetic linkage analysis in selected sibling- pairs 13 2.1 Introduction . . . 13

2.2 Methods . . . 16

2.3 Simulation studies . . . 21

2.4 Application to breast cancer data . . . 24

2.5 Discussion . . . 26

3 Robust age at onset linkage analysis in nuclear families 31 3.1 Introduction . . . 31

3.2 Methods . . . 33

3.3 Results . . . 35

3.4 Discussion . . . 43

4 New score tests for age-at-onset linkage analysis in general pedigrees 51 4.1 Background . . . 51

4.2 Methods . . . 52

4.3 Results . . . 55

4.4 Discussion . . . 56

4.5 Conclusions . . . 57

5 Weighted statistics for aggregation and linkage analysis of human longevity in selected families: The Leiden Longevity Study 59 5.1 Introduction . . . 60

5.2 Methods . . . 61

5.3 Results . . . 66

5.4 Discussion . . . 68 v

Contents

6 Allele-Sharing Statistics Using Information on Family History 73

6.1 Introduction . . . 73

6.2 Methods . . . 75

6.3 Power Study . . . 78

6.4 Data Analysis: Application to families with Symptomatic Os- teoarthritis . . . 79

6.5 Discussion . . . 80

7 Testing for genetic association in the presence of linkage and gene covariate interactions 87 7.1 Introduction . . . 87

7.2 The generalized linear mixed model . . . 89

7.3 Adjusting for gene-covariate interaction . . . 92

7.4 Results . . . 92

7.5 Discussion . . . 99

8 Summary 103 9 Samenvatting 105 A Arthur - Weighted Allele Sharing Methods for Genetic Linkage Anal- ysis 107 A.1 Introduction . . . 107

A.2 Methods . . . 108

A.3 Conclusion . . . 110

Bibliography 113

Curriculum Vitae 121

List of publications 123

vi