Ascertainment Bias in Genetic Pedigree Analysis

    Ascertainment bias is a systematic distortion  in measuring the true frequency of a phenomenon due to the way in which the data are collected. In genetics, ascertainment bias is an important factor in the use of family pedigree data to establish modes of inheritance.

    Consider the inheritance of  the genetic condition Alkaptonuria, characterized by excretion of high amounts of "alkapton" (Homogentisic Acid) in the urine. This is a autosomal recessive trait, such that almost all persons born with the condition (aa) will be the offspring of two unaffected heterozygous carrier (Aa) parents. Thus, according to ordinary Mendelian principles, among a large group of Aa x Aa crosses, 1/4 of offspring are expected to show the condition. Recognition of such a ratio would be an important clue to the pattern of inheritance.

    Alkaptonuria was the first human medical trait to be identified as genetic In the first inquiry into the genetics of this condition, Garrod (1902) reported the following data:

    Given the birth of offspring with alkaptonuria (aa) to "normal" parents, the parents must all be carriers (Aa). Then, among a total of 48 offspring of such parents, the expected ratio should be 1:3 or 12 alkaptonuric : 36 normal members. The observed ratio is 19 : 29, that is, significantly more alkaptonurics are present in the sample than expected from the genetic model. Why is this? The answer is the way in which Garrod collected his data, that is, the ascertainment bias.

    One source of ascertainment bias is that Garrod was a physician, and saw people who consulted him medically. His data tables includes only families in which at least one child has alkaptonuria. Because there is a 3/4 chance that any one child born to Aa parents will not have alkaptonuria, Garrod will not see this "zero class". The same is true for (3/4)2 = 9/16 and (3/4)3 = 27/64 of two- & three-child families. Thus large numbers of families with Aa parents and 1, 2, 3, or more unaffected children are excluded from his counts, and are underrepresented in his counts.

    A second source is the greater likelihood that families with a higher number of alkaptonuric children will consult Garrod: they are more likely to seek advice than families in which the condition is confined to a single child.  In the table, 6 of 9 families reported have more than one affected child, and in all of these (except family #7) the observed ratio of affected children exceeds 1:3. Indeed, without family #7, the observed proportion would be 18:20, effectively 1:1, which might imply autosomal dominant inheritance in which Aa x aa => 50% Aa: 50% aa. This will again systematically bias the data towards a higher proportion of affected children.

  A classroom demonstration of ascertainment bias is a survey for the primary sex ratio in humans.

Homework: (1) Test the deviation between Garrod's observed and expected results by the Chi-Square test. (2) How would you correct Garrod's data to test the hypothesis of recessive inheritance?

All text material ©2021 by Steven M. Carr