CS205: Building with Artificial Intelligence

In genetics, Bayes' rule can be used to estimate the probability of an individual having a specific genotype. Many people seek to approximate their chances of being affected by a genetic disease or their likelihood of being a carrier for a recessive gene of interest. A Bayesian analysis can be done based on family history or genetic testing, in order to predict whether an individual will develop a disease or pass one on to their children. Genetic testing and prediction is a common practice among couples who plan to have children but are concerned that they may both be carriers for a disease, especially within communities with low genetic variance.

The first step in Bayesian analysis for genetics is to propose mutually exclusive hypotheses: for a specific allele, an individual either is or is not a carrier. Next, four probabilities are calculated: Prior Probability (the likelihood of each hypothesis considering information such as family history or predictions based on Mendelian Inheritance), Conditional Probability (of a certain outcome), Joint Probability (product of the first two), and Posterior Probability (a weighted product calculated by dividing the Joint Probability for each hypothesis by the sum of both joint probabilities). This type of analysis can be done based purely on family history of a condition or in concert with genetic testing.

Using pedigree to calculate probabilities

Example of a Bayesian analysis table for a female individual's risk for a disease based on the knowledge that the disease is present in her siblings but not in her parents or any of her four children. Based solely on the status of the subject's siblings and parents, she is equally likely to be a carrier as to be a non-carrier (this likelihood is denoted by the Prior Hypothesis). However, the probability that the subject's four sons would all be unaffected is 1/16 (1⁄2·1⁄2·1⁄2·1⁄2) if she is a carrier, about 1 if she is a non-carrier (this is the Conditional Probability). The Joint Probability reconciles these two predictions by multiplying them together. The last line (the Posterior Probability) is calculated by dividing the Joint Probability for each hypothesis by the sum of both joint probabilities.

Using genetic test results

Parental genetic testing can detect around 90% of known disease alleles in parents that can lead to carrier or affected status in their child. Cystic fibrosis is a heritable disease caused by an autosomal recessive mutation on the CFTR gene, located on the q arm of chromosome 7.

Bayesian analysis of a female patient with a family history of cystic fibrosis (CF), who has tested negative for CF, demonstrating how this method was used to determine her risk of having a child born with CF:

Because the patient is unaffected, she is either homozygous for the wild-type allele, or heterozygous. To establish prior probabilities, a Punnett square is used, based on the knowledge that neither parent was affected by the disease but both could have been carriers:

Given that the patient is unaffected, there are only three possibilities. Within these three, there are two scenarios in which the patient carries the mutant allele. Thus the prior probabilities are 2⁄3 and 1⁄3.

Next, the patient undergoes genetic testing and tests negative for cystic fibrosis. This test has a 90% detection rate, so the conditional probabilities of a negative test are 1/10 and 1.  Finally, the joint and posterior probabilities are calculated as before.

After carrying out the same analysis on the patient's male partner (with a negative test result), the chances of their child being affected is equal to the product of the parents' respective posterior probabilities for being carriers times the chances that two carriers will produce an affected offspring (1⁄4).

Genetic testing done in parallel with other risk factor identification

Bayesian analysis can be done using phenotypic information associated with a genetic condition, and when combined with genetic testing this analysis becomes much more complicated. Cystic fibrosis, for example, can be identified in a fetus through an ultrasound looking for an echogenic bowel, meaning one that appears brighter than normal on a scan. This is not a foolproof test, as an echogenic bowel can be present in a perfectly healthy fetus. Parental genetic testing is very influential in this case, where a phenotypic facet can be overly influential in probability calculation. In the case of a fetus with an echogenic bowel, with a mother who has been tested and is known to be a CF carrier, the posterior probability that the fetus actually has the disease is very high (0.64). However, once the father has tested negative for CF, the posterior probability drops significantly (to 0.16).

Risk factor calculation is a powerful tool in genetic counseling and reproductive planning, but it cannot be treated as the only important factor to consider. As above, incomplete testing can yield falsely high probability of carrier status, and testing can be financially inaccessible or unfeasible when a parent is not present.