Bayesian Analysis Used in Risk Modification

When collected pedigrees are used to provide risk assessment, a variety of data may be relevant to the overall assessment. Numerous factors, some listed above, influence the likelihood that a given individual in the family may be affected by the condition in question or may be a carrier of the gene in question. When it is not possible to do direct diagnostic testing for the condition (for example, if the causative gene is unknown), when the affected relative is not available for testing, or for complex traits, it is possible to combine incremental contributors to risk by utilizing Bayesian analysis. Bayesian analysis is a statistical construct that uses information about the likelihood of occurrence of past events or conditions, and the current status of those events or conditions for the individual, to predict the likelihood of a future event or condition, in this case, the presence or absence of a particular gene or genetic condition.18 Some factors that may be considered in genetic risk assessment using Bayesian analysis include number and pattern of affected and unaffected family members, laboratory data, and natural history of the condition. The probability assigned based on past events is called the prior probability; that based on current information or observations is called the conditional probability. The calculated probability for each possible outcome of an event or condition is the joint probability, and the final probability of one outcome as a percentage of all possible outcomes is the posterior probability. Calculations often utilize data from multiple generations and are usually done in tabular form. In the example pedigree in Figure 4-7 for an autosomal dominant cancer predisposition syndrome affecting males and females equally, based on Mendelian inheritance alone, the risk that individual III.5 is a gene carrier is 25%. However, knowing that 75% of gene carriers have been diagnosed with cancer by age 50, risk can be recalculated as demonstrated. (See chapter 5 for a complete discussion of Bayesian analysis.)

1234 '5 6789 10

For ll.3

Gene present

Gene not present

Prior probability

1/2

1/2

Conditional probability

1/4

1

Joint probability

1/8

1/2

1/8+1/2

1/8 +1/2

Posterior probability

1/5 =20%

4/5 =20%

For lll.5

/5x1/2=1/10=10%

Figure 4-7. Bayesian analysis for risk assessment in an autosomal dominant, adult-onset hereditary cancer disorder. Ages of selected individuals in generation II are shown below the pedigree symbols.

References

1. Resta R. The crane's foot: the rise of the pedigree in human genetics. J Genet Couns. 1993;2:235-260.

2. Bennett R, Steinhaus K, Uhrich S, O'Sullivan C. The need for developing standardized family pedigree nomenclature. J Genet Couns. 1993;2:261-273.

3. Bennett R, Steinhaus K, Uhrich S, et al. Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors. Am JHum Genet. 1995;56:745-752.

4. Bennett R. The Language of the Pedigree: The Practical Guide to the Genetic Family History. New York: Wiley-Liss; 1999:1-12.

Daly M, Farmer J, Harrop-Stein C, et al. Exploring family relationships in cancer risk counseling using the genogram. Cancer Epidemiol Biomarkers Prev 1999;8:393-398.

Botkin J. Protecting the privacy of family members in survey and pedigree research. JAMA. 2001;285:207-211.

American Society of Human Genetics Policy Papers and Reports. Should Family Members About Whom You Collect Only Medical History Information for Your Research Be Considered "Human Subjects"? Amercian Society of Human Genetics, Bethesda, MD, 2000. http://www.ashg.org/genetics/ashg/pubs/policy/pol-38.htm US Department of Health and Human Services. Medical Privacy— National Standards to Protect the Privacy of Personal Health Information. US Department of Health and Human Services; 2003. ASHG statement. Professional disclosure of familial genetic information. The American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure. Am JHum Genet. 1998;63:898-900. Vogel F, Motulsky A. Human Genetics: Problems and Approaches. Berlin: Springer-Verlag; 1997.

McKusick V. Online Mendelian Inheritance in Man, OMIM [database online]. Baltimore, MD: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University; Bethesda, MD: National Center for Biotechnology Information, National Library of Medicine, 1966-2005.

Tommerup N. Mendelian cytogenetics: chromosome rearrangements associated with Mendelian disorders. J Med Genet. 1993;30: 713-727.

Schmickel R. Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr. 1986;109:231-241. Nussbaum R, McInnes R, Willard H. Thompson & Thompson Genetics in Medicine. Philadelphia: W.B. Saunders; 2001. Vockley J, Rinaldo P, Bennett M, Matern D, Vladutiu G. Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathway. Mol Genet Metab. 2000;71:10-18. Bennett R, Motulsky A, Bittles A, et al. Genetic counseling and screening of consanguineous couples and their offspring: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2002;11:97-120.

Beaudet A, Scriver C, Sly W, Valle D. Genetics, biochemistry and molecular basis of variant human phenotypes. In: Beaudet A, Scriver C, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol. 1. New York: McGraw-Hill, 2001:14-42. Young I. Genetic Counseling and the Laws of Probability. Introduction to Risk Calculation in Genetic Counseling. Oxford: Oxford University Press; 1999:1-14.

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