Family Cosegregation Analysis - Background

This website ( implements various methods for cosegregation analysis. Each method analyzes a pedigree and gives a value that can be used to determine whether a variant is pathogenic or benign.

Scores generated by the Full Likelihood Bayes (FLB) (Thompson 2003) and Cosegregation Likelihood Ratio (CSLR) (Mohammadi 2009) methods can be used as Bayes factors, with scores > 1 indicating increased likelihood that a variant is pathogenic and < 1 indicating likelihood that a variant is benign. Likelihood ratios and bayes factors can both be used in qualitative Bayesian analysis of a variant. For more information please refer to the references below. Note that the FLB method on the website is built upon the LINKAGE or FASTLINK program, and the CSLR and meioses counting methods use the CoSeg R package. References for those software programs are also listed below.

For a comparison of these three methods see RaƱola JMO, Liu Q, Rosenthal EA, and Shirts BH. A comparison of cosegregation analysis methods for the clinical setting Fam Cancer. 2018 4;17(2):295-302. PMID:28695303 6. Briefly, the FLB and CLSR methods usually create similar output and are preferred over counting meiosis. In the implementation on this site, FLB is more robust to complex family structures, so is more likekly to be accurate.

  • CSLR: Mohammadi L, Vreeswijk MP, Oldenburg R, et al. A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example. BMC Cancer. 2009;9:211. PMID:19563646
  • FLB: Thompson D, Easton DF, Goldgar DE. A full-likelihood method for the evaluation of causality of sequence variants from family data. Am J Hum Genet. 2003;73(3):652-655.PMID:12900794
  • Meioses Counting: Jarvik GP, Browning BL. Consideration of cosegregation in the pathogenicity classification of genomic variants. Am J Hum Genet. 2016;98(6):1077-1081.PMID:27236918
  • FLB (Fastlink): Schaffer AA, Gupta SK, Shriram K, Cottingham RW. Avoiding recomputation in linkage analysis. Hum Hered. 1994;44(4):225-237. PMID:8056435
  • FLB (LINKAGE): Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984;36(2):460-465.PMID:6585139
  • CSLR/Meioses Counting and CoSeg R package: Ranola JM, Liu Q, Rosenthal E, and Shirts B. A comparison of cosegregation analysis methods for the clinical setting. Familial Cancer. 2017; In press.PMID:28695303
  • Population-Level Penetrance Estimates: Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD,, based on November 2016 SEER data submission, posted to the SEER web site, April 2017
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