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Vol. 66, No. 4, 2008
Issue release date: October 2008
Free Access
Hum Hered 2008;66:223–237
(DOI:10.1159/000143405)

Practical Considerations for Dividing Data into Subsets Prior to PPL Analysis

Govil M.a · Vieland V.J.b
aDepartment of Oral Biology and Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pa., bBattelle Center of Mathematical Medicine, The Research Institute at Nationwide Children’s Hospital and The Ohio State University, Columbus, Ohio, USA
email Corresponding Author

Abstract

Objective: The PPL, a class of statistics for complex trait genetic mapping in humans, utilizes Bayesian sequential updating to accumulate evidence for or against linkage across potentially heterogeneous data (sub)sets. Here, we systematically explore the relative efficacy of alternative subsetting approaches for purposes of PPL calculation. Methods: We simulated genotypes for three pedigree sets (sib pairs; 2–3 generations; ≧4 generations) based on families from an ongoing study. For each pedigree set, 100 replicates were generated under different levels of heterogeneity (1000 under ‘no linkage’). Within each replicate, updating was performed across subsets defined randomly (RAND2, RAND4), by true (TRUE) linkage status, with a realistic (REAL) classification, by individual pedigree (PED), or without any subsetting (NONE). Results: Under ‘linkage’, REAL yields larger PPLs compared to NONE, RAND2, RAND4, or PED. Under ‘no linkage’, RAND2, RAND4 and PED yield PPLs close to NONE. Conclusions: We have examined the impact of different subsetting strategies on the sampling behavior of the PPL. Our results underscore the utility of finding variables that can help delineate more homogeneous data subsets and demonstrate that, once such variables are found, sequential updating can be highly beneficial in the presence of appreciable heterogeneity at a linked locus, without inflation at an unlinked locus.


 goto top of outline Key Words

  • Complex traits
  • Linkage analysis
  • Genetic mapping
  • Posterior probability of linkage
  • PPL
  • Sequential updating
  • Heterogeneity
  • Clinically defined subsets
  • Bayesian linkage analysis

 goto top of outline Abstract

Objective: The PPL, a class of statistics for complex trait genetic mapping in humans, utilizes Bayesian sequential updating to accumulate evidence for or against linkage across potentially heterogeneous data (sub)sets. Here, we systematically explore the relative efficacy of alternative subsetting approaches for purposes of PPL calculation. Methods: We simulated genotypes for three pedigree sets (sib pairs; 2–3 generations; ≥4 generations) based on families from an ongoing study. For each pedigree set, 100 replicates were generated under different levels of heterogeneity (1000 under ‘no linkage’). Within each replicate, updating was performed across subsets defined randomly (RAND2, RAND4), by true (TRUE) linkage status, with a realistic (REAL) classification, by individual pedigree (PED), or without any subsetting (NONE). Results: Under ‘linkage’, REAL yields larger PPLs compared to NONE, RAND2, RAND4, or PED. Under ‘no linkage’, RAND2, RAND4 and PED yield PPLs close to NONE. Conclusions: We have examined the impact of different subsetting strategies on the sampling behavior of the PPL. Our results underscore the utility of finding variables that can help delineate more homogeneous data subsets and demonstrate that, once such variables are found, sequential updating can be highly beneficial in the presence of appreciable heterogeneity at a linked locus, without inflation at an unlinked locus.

Copyright © 2008 S. Karger AG, Basel


 goto top of outline References
  1. 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.
  2. Vieland VJ: Thermometers: something for statistical geneticists to think about. Hum Hered 2006;61:144–156.
  3. Logue MW, Vieland VJ: A new method for computing the multipoint posterior probability of linkage. Hum Hered 2004;57:90–99.
  4. Bartlett CW, Vieland VJ: Accumulating quantitative trait linkage evidence across multiple datasets using the posterior probability of linkage. Genet Epidemiol 2007;31:91–102.
  5. 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.
  6. Huang Y, Bartlett CW, Segre AM, O’Connell JR, Mangin L, Vieland VJ: Exploiting gene × gene interaction in linkage analysis. BMC Proceedings 2007;1(suppl 1):S64.
  7. Yang X, Huang J, Logue MW, Vieland VJ: 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.
  8. 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.
  9. Govil M: Extensions of the posterior probability of linkage: Distributed computation, incorporation of genetic map information, and application to cleft lip and/or palate, Doctoral Thesis 2005; The University of Iowa.
  10. 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.
  11. 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.
  12. Wang K, Vieland VJ, Huang J: A Bayesian approach to replication of linkage findings. Genet Epidemiol 1999;17(suppl 1):S749–S754.
  13. Marazita ML, Murray JC, Lidral AC, Arcos-Burgos M, Cooper ME, Goldstein T, Maher BS, Daack-Hirsch S, Schultz R, Mansilla MA, Field LL, Liu YE, Prescott N, Malcolm S, Winter R, Ray A, Moreno L, Valencia C, Neiswanger K, Wyszynski DF, Bailey-Wilson JE, Albacha-Hejazi H, Beaty TH, McIntosh I, Hetmanski JB, Tuncbilek G, Edwards M, Harkin L, Scott R, Roddick LG: Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32–35. Am J Hum Genet 2004;75:161–173.
  14. Mitchell LE, Risch N: Mode of inheritance of non-syndromic cleft lip with or without cleft palate: A reanalysis. Am J Hum Genet 1992;51:323–332.
  15. Wyszynski DF, Beaty TH: Review of the role of potential teratogens in the origin of human nonsyndromic oral clefts. Teratology 1996;53:309–317.
  16. Little J, Cardy A, Munger RG: Tobacco smoking and oral clefts: A meta-analysis. Bull World Health Organ 2004;82:213–218.
  17. Ott J: Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci USA 1989;86:4175–4178.
  18. Weeks, DE, Ott J, Lathrop GM: SLINK: A general simulation program for linkage analysis. Am J Hum Genet 1990;47(suppl 3):A204.
  19. Smith CAB: Testing for heterogeneity of recombination fraction values in human genetics. Ann Hum Genet 1963;27:175–192.
  20. Clerget-Darpoux F, Bonaïti-Pellié C, Hochez J: Effects of misspecifying genetic parameters in LOD Score Analysis. Biometrics 1986;42:393–399.
  21. Greenberg DA: Inferring mode of inheritance by comparison of LOD scores. Am J Med Genet 1989;34:480–486.
  22. Elston RC: Man bites dog? The validity of maximizing LOD scores to determine mode of inheritance. Am J Med Genet 1989;34:487–488.
  23. Ott J: Analysis of Human Genetic Linkage, ed 2, revised. Baltimore, The Johns Hopkins University Press, 1991.
  24. Govil M, Segre AM, Vieland VJ: MLIP: A multiprocessor linkage analysis system. Proceedings of IEEE 2nd International Multi-Symposiums on Computer and Computational Sciences (IMSCCS 2007); pp 17–24, August 13–15, 2007, Iowa City, IA, USA. Available: http://ieeexplore.ieee.org/search/srchabstract.jsp?arnumber=4392575&isnumber=4392566&punumber=4392565& k2dockey=4392575@ieeecnfs@query=%28 govil+%3Cin%3E+metadata%29+%3Cand%3E+%284392565+%3Cin%3E+punumber%29&pos=0&access=no
  25. Huang Y, Segre AM, O’Connell JR, Wang H, Vieland VJ: KELVIN: A 2nd generation distributed multiprocessor linkage and linkage disequilibrium analysis program [abstract 1556]. Presented at the annual meeting of The American Society of Human Genetics; October 9–13, 2006, New Orleans, LA, USA. Available from: http://www.ashg.org/genetics/ashg06s/index.shtml.
  26. Wang H, Segre AM, Huang Y, O’Connell JR, Vieland VJ: Fast computation of human genetic linkage. Proceedings of IEEE 7th Symposium on Bioinformatics and Bioengineering (BIBE 2007); pp 857–863, October 14–17, 2007, Boston, MA, USA. Available: http://ieeexplore.ieee.org/search/srchabstract.jsp? arnumber=4375660&isnumber=4375521& punumber=4375520&k2dockey=4375660@ ieeecnfs&query=%28vieland+%3Cin%3E+ metadata%29+%3Cand%3E+%284375520+%3Cin%3E+punumber%29&pos=0&access=no
  27. Wang K, Huang J, Vieland VJ: The consistency of the posterior probability of linkage. Am J Hum Genet 2000;64:533–553.
  28. Logue MW, Vieland VJ, Goedken RJ, Crowe RR: 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 Neuropsychiatr Genet 2003;121B:95–99.
  29. Elston RC, Lange K: The prior probability of autosomal linkage. Ann Hum Genet 1975;38:341–350.
  30. Bartlett CW, Flax JF, Logue MW, Vieland VJ, Bassett AS, Tallal P, Brzustowicz LM: A major susceptibility locus for specific language impairment is located on 13q21. Am J Hum Genet 2002;71:45–55.

 goto top of outline Author Contacts

Manika Govil
Suite 500 Cellomics/Bridgeside Point
100 Technology Drive
Pittsburgh, PA 15219 (USA)
Tel. +1 412 648 9204, Fax +1 412 648 8779, E-Mail govil@pitt.edu


 goto top of outline Article Information

Received: September 24, 2007
Accepted after revision: November 16, 2007
Published online: July 9, 2008
Number of Print Pages : 15
Number of Figures : 5, Number of Tables : 6, Number of References : 30


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 66, No. 4, Year 2008 (Cover Date: October 2008)

Journal Editor: Devoto M. (Philadelphia, Pa.)
ISSN: 0001–5652 (Print), eISSN: 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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.

Abstract

Objective: The PPL, a class of statistics for complex trait genetic mapping in humans, utilizes Bayesian sequential updating to accumulate evidence for or against linkage across potentially heterogeneous data (sub)sets. Here, we systematically explore the relative efficacy of alternative subsetting approaches for purposes of PPL calculation. Methods: We simulated genotypes for three pedigree sets (sib pairs; 2–3 generations; ≧4 generations) based on families from an ongoing study. For each pedigree set, 100 replicates were generated under different levels of heterogeneity (1000 under ‘no linkage’). Within each replicate, updating was performed across subsets defined randomly (RAND2, RAND4), by true (TRUE) linkage status, with a realistic (REAL) classification, by individual pedigree (PED), or without any subsetting (NONE). Results: Under ‘linkage’, REAL yields larger PPLs compared to NONE, RAND2, RAND4, or PED. Under ‘no linkage’, RAND2, RAND4 and PED yield PPLs close to NONE. Conclusions: We have examined the impact of different subsetting strategies on the sampling behavior of the PPL. Our results underscore the utility of finding variables that can help delineate more homogeneous data subsets and demonstrate that, once such variables are found, sequential updating can be highly beneficial in the presence of appreciable heterogeneity at a linked locus, without inflation at an unlinked locus.



 goto top of outline Author Contacts

Manika Govil
Suite 500 Cellomics/Bridgeside Point
100 Technology Drive
Pittsburgh, PA 15219 (USA)
Tel. +1 412 648 9204, Fax +1 412 648 8779, E-Mail govil@pitt.edu


 goto top of outline Article Information

Received: September 24, 2007
Accepted after revision: November 16, 2007
Published online: July 9, 2008
Number of Print Pages : 15
Number of Figures : 5, Number of Tables : 6, Number of References : 30


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 66, No. 4, Year 2008 (Cover Date: October 2008)

Journal Editor: Devoto M. (Philadelphia, Pa.)
ISSN: 0001–5652 (Print), eISSN: 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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.

References

  1. 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.
  2. Vieland VJ: Thermometers: something for statistical geneticists to think about. Hum Hered 2006;61:144–156.
  3. Logue MW, Vieland VJ: A new method for computing the multipoint posterior probability of linkage. Hum Hered 2004;57:90–99.
  4. Bartlett CW, Vieland VJ: Accumulating quantitative trait linkage evidence across multiple datasets using the posterior probability of linkage. Genet Epidemiol 2007;31:91–102.
  5. 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.
  6. Huang Y, Bartlett CW, Segre AM, O’Connell JR, Mangin L, Vieland VJ: Exploiting gene × gene interaction in linkage analysis. BMC Proceedings 2007;1(suppl 1):S64.
  7. Yang X, Huang J, Logue MW, Vieland VJ: 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.
  8. 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.
  9. Govil M: Extensions of the posterior probability of linkage: Distributed computation, incorporation of genetic map information, and application to cleft lip and/or palate, Doctoral Thesis 2005; The University of Iowa.
  10. 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.
  11. 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.
  12. Wang K, Vieland VJ, Huang J: A Bayesian approach to replication of linkage findings. Genet Epidemiol 1999;17(suppl 1):S749–S754.
  13. Marazita ML, Murray JC, Lidral AC, Arcos-Burgos M, Cooper ME, Goldstein T, Maher BS, Daack-Hirsch S, Schultz R, Mansilla MA, Field LL, Liu YE, Prescott N, Malcolm S, Winter R, Ray A, Moreno L, Valencia C, Neiswanger K, Wyszynski DF, Bailey-Wilson JE, Albacha-Hejazi H, Beaty TH, McIntosh I, Hetmanski JB, Tuncbilek G, Edwards M, Harkin L, Scott R, Roddick LG: Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32–35. Am J Hum Genet 2004;75:161–173.
  14. Mitchell LE, Risch N: Mode of inheritance of non-syndromic cleft lip with or without cleft palate: A reanalysis. Am J Hum Genet 1992;51:323–332.
  15. Wyszynski DF, Beaty TH: Review of the role of potential teratogens in the origin of human nonsyndromic oral clefts. Teratology 1996;53:309–317.
  16. Little J, Cardy A, Munger RG: Tobacco smoking and oral clefts: A meta-analysis. Bull World Health Organ 2004;82:213–218.
  17. Ott J: Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci USA 1989;86:4175–4178.
  18. Weeks, DE, Ott J, Lathrop GM: SLINK: A general simulation program for linkage analysis. Am J Hum Genet 1990;47(suppl 3):A204.
  19. Smith CAB: Testing for heterogeneity of recombination fraction values in human genetics. Ann Hum Genet 1963;27:175–192.
  20. Clerget-Darpoux F, Bonaïti-Pellié C, Hochez J: Effects of misspecifying genetic parameters in LOD Score Analysis. Biometrics 1986;42:393–399.
  21. Greenberg DA: Inferring mode of inheritance by comparison of LOD scores. Am J Med Genet 1989;34:480–486.
  22. Elston RC: Man bites dog? The validity of maximizing LOD scores to determine mode of inheritance. Am J Med Genet 1989;34:487–488.
  23. Ott J: Analysis of Human Genetic Linkage, ed 2, revised. Baltimore, The Johns Hopkins University Press, 1991.
  24. Govil M, Segre AM, Vieland VJ: MLIP: A multiprocessor linkage analysis system. Proceedings of IEEE 2nd International Multi-Symposiums on Computer and Computational Sciences (IMSCCS 2007); pp 17–24, August 13–15, 2007, Iowa City, IA, USA. Available: http://ieeexplore.ieee.org/search/srchabstract.jsp?arnumber=4392575&isnumber=4392566&punumber=4392565& k2dockey=4392575@ieeecnfs@query=%28 govil+%3Cin%3E+metadata%29+%3Cand%3E+%284392565+%3Cin%3E+punumber%29&pos=0&access=no
  25. Huang Y, Segre AM, O’Connell JR, Wang H, Vieland VJ: KELVIN: A 2nd generation distributed multiprocessor linkage and linkage disequilibrium analysis program [abstract 1556]. Presented at the annual meeting of The American Society of Human Genetics; October 9–13, 2006, New Orleans, LA, USA. Available from: http://www.ashg.org/genetics/ashg06s/index.shtml.
  26. Wang H, Segre AM, Huang Y, O’Connell JR, Vieland VJ: Fast computation of human genetic linkage. Proceedings of IEEE 7th Symposium on Bioinformatics and Bioengineering (BIBE 2007); pp 857–863, October 14–17, 2007, Boston, MA, USA. Available: http://ieeexplore.ieee.org/search/srchabstract.jsp? arnumber=4375660&isnumber=4375521& punumber=4375520&k2dockey=4375660@ ieeecnfs&query=%28vieland+%3Cin%3E+ metadata%29+%3Cand%3E+%284375520+%3Cin%3E+punumber%29&pos=0&access=no
  27. Wang K, Huang J, Vieland VJ: The consistency of the posterior probability of linkage. Am J Hum Genet 2000;64:533–553.
  28. Logue MW, Vieland VJ, Goedken RJ, Crowe RR: 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 Neuropsychiatr Genet 2003;121B:95–99.
  29. Elston RC, Lange K: The prior probability of autosomal linkage. Ann Hum Genet 1975;38:341–350.
  30. Bartlett CW, Flax JF, Logue MW, Vieland VJ, Bassett AS, Tallal P, Brzustowicz LM: A major susceptibility locus for specific language impairment is located on 13q21. Am J Hum Genet 2002;71:45–55.