This paper describes the software package KELVIN, which supports the PPL (posterior probability of linkage) framework for the measurement of statistical evidence in human (or more generally, diploid) genetic studies. In terms of scope, KELVIN supports two-point (trait-marker or marker-marker) and multipoint linkage analysis, based on either sex-averaged or sex-specific genetic maps, with an option to allow for imprinting; trait-marker linkage disequilibrium (LD), or association analysis, in case-control data, trio data, and/or multiplex family data, with options for joint linkage and trait-marker LD or conditional LD given linkage; dichotomous trait, quantitative trait and quantitative trait threshold models; and certain types of gene-gene interactions and covariate effects. Features and data (pedigree) structures can be freely mixed and matched within analyses. The statistical framework is specifically tailored to accumulate evidence in a mathematically rigorous way across multiple data sets or data subsets while allowing for multiple sources of heterogeneity, and KELVIN itself utilizes sophisticated software engineering to provide a powerful and robust platform for studying the genetics of complex disorders.
© 2011 S. Karger AG, Basel
- Linkage disequilibrium
- Quantitative traits
- Statistical evidence
- Elston RC, Stewart J: A general model for the genetic analysis of pedigree data. Hum Hered 1971;21:523–542.
- Logue MW, Vieland VJ: A new method for computing the multipoint posterior probability of linkage. Hum Hered 2004;57:90–99.
- George AW, et al: Calculation of multipoint likelihoods using flanking marker data: a simulation study. BMC Genet 2005;6(suppl 1):S44.
- Lander ES, Green P: Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci USA 1987;84:2363–2367.
- Vieland VJ: Thermometers: something for statistical geneticists to think about. Hum Hered 2006;61:144–156.
- Vieland VJ: Where’s the evidence? Hum Hered 2011;71:59–66.
- Vieland VJ, Hodge SE: Review of statistical evidence: a likelihood paradigm. Am J Hum Genet 1998;63:283–289.
- Vieland VJ: Bayesian linkage analysis, or: how I learned to stop worrying and love the posterior probability of linkage. Am J Hum Genet 1998;63:947–954.
- Smith CAB: Some comments on the statistical methods used in linkage investigations. Am J Hum Genet 1959;11:289–304.
- Greenberg DA: Inferring mode of inheritance by comparison of lod scores. Am J Med Genet 1989;34:480–486.
- Elston RC: Man bites dog? The validity of maximizing lod scores to determine mode of inheritance. Am J Med Genet 1989;34:487–488.
- Ewens WJ, Shute NC: A resolution of the ascertainment sampling problem. I. Theory. Theor Popul Biol 1986;30:388–412.
- Vieland VJ, Hodge SE: The problem of ascertainment for linkage analysis. Am J Hum Genet 1996;58:1072–1084.
- Vieland VJ, Hodge SE: Ascertainment bias in linkage analysis: comments on Ginsburg et al. Genet Epi 2005;28:283–285.
- Wang K: PhD thesis paper. University of Iowa, 1999.
- Elston RC, Lange K: The prior probability of autosomal linkage. Ann Hum Genet 1975;38:341–350.
- Vieland VJ, et al: A multilocus model of the genetic architecture of autoimmune thyroid disorder, with clinical implications. Am J Hum Genet 2008;82:1349–1356.
- Wratten NS, et al: Identification of a schizophrenia-associated functional noncoding variant in NOS1AP. Am J Psychiatry 2009;166:434–441.
- Vieland VJ, et al: Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism. J Neurodev Disord 2011;3:113–123.
- Pagnamenta AT, et al: Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability. J Med Genet 2011;48:48–54.
- Smith CAB: Testing for heterogeneity of recombination fraction values in human genetics. Ann Hum Genet 1963;27:175–182.
- Hodge SE, et al: The search for heterogeneity in insulin-dependent diabetes mellitus (IDDM): linkage studies, two-locus models, and genetic heterogeneity. Am J Hum Genet 1983;35:1139–1155.
- Vieland VJ, Logue M: HLODs, trait models, and ascertainment: implications of admixture for parameter estimation and linkage detection. Hum Hered 2002;53:23–35.
- Ott J: Linkage analysis and family classification under heterogeneity. Ann Hum Genet 1983;47:311–320.
- Vieland VJ: The replication requirement. Nat Genet 2001;29:244–245.
- Hodge SE, Vieland VJ: Expected monotonicity – a desirable property for evidence measures? Hum Hered 2010;70:151–166.
- Wang K, Huang J, Vieland VJ: The consistency of the posterior probability of linkage. Ann Hum Genet 2000;64:533–553.
- Vieland VJ, Wang K, Huang J: Power to detect linkage based on multiple sets of data in the presence of locus heterogeneity: comparative evaluation of model-based linkage methods for affected sib pair data. Hum Hered 2001;51:199–208.
- Huang J, Vieland VJ: Comparison of ‘model-free’ and ‘model-based’ linkage statistics in the presence of locus heterogeneity: single data set and multiple data set applications. Hum Hered 2001;51:217–225.
- Bartlett CW, Goedken R, Vieland VJ: Effects of updating linkage evidence across subsets of data: reanalysis of the autism genetic resource exchange data set. Am J Hum Genet 2005;76:688–695.
- Govil M, Vieland VJ: Practical considerations for dividing data into subsets prior to PPL analysis. Hum Hered 2008;66:223–237.
- Huang Y, Vieland VJ: Association statistics under the PPL framework. Genet Epidemiol 2010;34:835–845.
- Wang K, Vieland V, Huang J: A Bayesian approach to replication of linkage findings. Genet Epidemiol 1999;17(suppl 1):S749–S754.
- Greenberg DA: Summary of analyses of problem 2 simulated data for GAW 11. Genet Epidemiol 1999;17(suppl 1):S449–S459.
- Logue MW, Vieland VJ: The incorporation of prior genomic information does not necessarily improve the performance of Bayesian linkage methods: an example involving sex-specific recombination and the two-point PPL. Hum Hered 2005;60:196–205.
- Greenberg DA, Hodge SE: Linkage analysis under ‘random’ and ‘genetic’ reduced penetrance. Genet Epidemiol 1989;6:259–264.
- Vieland VJ, Hodge SE, Greenberg DA: Adequacy of single-locus approximations for linkage analyses of oligogenic traits. Genet Epidemiol 1992;9:45–59.
- Vieland VJ, Greenberg DA, Hodge SE: Adequacy of single-locus approximations for linkage analyses of oligogenic traits: extension to multigenerational pedigree structures. Hum Hered 1993;43:329–336.
- Slager SL, Vieland VJ: Investigating the numerical effects of ascertainment bias in linkage analysis: development of methods and preliminary results. Genet Epidemiol 1997;14:1119–1124.
- Clerget-Darpoux F, Bonaiti-Pellie C, Hochez J: Effects of misspecifying genetic parameters in lod score analysis. Biometrics 1986;42:393–399.
- Logue M, et al: Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7. Am J Med Genet B (Neuropsychiat Genet) 2003;121B:95–99.
- Logue MW: Complications of an unknown genetic model in the presence of heterogeneity for linkage analysis [Ph.D. dissertation]. University of Iowa: Iowa City, 2001, p 124.
- Logue M, et al: A posterior probability of linkage-based re-analysis of schizophrenia data yields evidence of linkage to chromosomes 1 and 17. Hum Hered 2006;62:47–54.
- Ott J: A computer program for linkage analysis of general human pedigrees. Am J Hum Genet 1976;28:528–529.
- Bartlett CW, Vieland VJ: Accumulating quantitative trait linkage evidence across multiple datasets using the posterior probability of linkage. Genet Epi 2006;31:91–102.
- Bartlett CW, Vieland VJ: Two novel quantitative trait linkage analysis statistics based on the posterior probability of linkage: application to the COGA families. BMC Genet 2005;6(suppl 1):S121.
- Huang Y, et al: Exploiting gene x gene interaction in linkage analysis. BMC Proceedings 2007;1(suppl 1):S64(1–5).
- Vieland VJ, Huang J: Two-locus heterogeneity cannot be distinguished from two-locus epistasis on the basis of affected-sib-pair data. Am J Hum Genet 2003;73:223–232.
- Vieland VJ, Huang J: Reply to Cordell and Farrall. Am J Hum Genet 2003;73:1471–1473.
- Lewontin RC: The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 1964;49:49–67.
- Slager SL, Huang J, Vieland VJ: Power comparisons between the TDT and two likelihood-based methods. Genet Epidemiol 2001;20:192–209.
- Yang X, et al: The posterior probability of linkage allowing for linkage disequilibrium and a new estimate of disequilibrium between a trait and a marker. Hum Hered 2005;59:210–219.
- Flax JF, et al: Combined linkage and linkage disequilibrium analysis of a motor speech phenotype within families ascertained for autism risk loci. J Neurodev Disord 2010;2:210–223.
- O’Connell J, Weeks D: The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nat Genet 1995;11:402–408.
- O’Connell J: Rapid multipoint linkage analysis via inheritance vectors in the Elston-Stewart algorithm. Hum Hered 2001;51:226–240.
- Huang Y, et al: KELVIN: a 2nd generation distributed multiprocessor linkage and linkage disequilibrium analysis program. Presented at the annual meeting of The American Society of Human Genetics. New Orleans, 2006.
- Kruglyak L, et al: Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996;58:1347–1363.
- Wang H, et al: Fast computation of human genetic linkage. Proceedings of the 7th IEEE Symposium on Bioinformatics and Bioengineering, 2007. BIBE 2007, pp 857–863.
- Wang H, et al: Rapid computation of large numbers of LOD scores in linkage analysis through polynomial expression of genetic likelihoods. Proceedings of IEEE Workshop on High-Throughput Data Analysis for Proteomics and Genomics, 2007. IEEE 2007, pp 197–204.
- Kramer RW, Weeks DE, Chiarulli DM: An incremental algorithm for efficient multipoint linkage analysis. Hum Hered 1995;45:323–336.
- Bernsten J, Espelid T, Genz A: An adaptive multidimensional integration routine for a vector of integrals. ACM Trans Math Softw 1991;17:452–456.
- Seok S-C, Evans M, Vieland VJ: Fast and accurate calculation of a computationally intensive statistic for mapping disease genes. J Comput Biol 2009;16:659–676.
- Hodge SE, Vieland VJ: Expected monotonicity – a desirable property for evidence measures? Hum Hered 2010;70:151–166.
- Vieland VJ, Hodge SE: Measurement of evidence and evidence of measurement (Invited Commentary). Stat Appl Genet Mol Biol 2011;10:Article 35.
Veronica J. Vieland, PhD
Research Institute at Nationwide Children’s Hospital
700 Children’s Drive
Columbus, OH 43205 (USA)
Tel. +1 614 355 2861, E-Mail Veronica.Vieland@nationwidechildrens.org
Published online: December 23, 2011
Number of Print Pages : 13
Number of Figures : 6, Number of Tables : 0, Number of References : 64
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 72, No. 4, Year 2011 (Cover Date: December 2011)
Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)
For additional information: http://www.karger.com/HHE
Open Access License / Drug Dosage / Disclaimer
Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license
), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.