Only when an individual attends clinic is it possible to be sure that they are aware of their family history and the implications it may have for them. It may be preferable to measure uptake as a proportion of those who have attended clinic, rather than of the whole family. This would change the equation to: Ui= n/C, where U is the uptake amongst people known to have received counselling about testing, and C is the total number who have had counselling. If this were the calculation used, then the relationship between N and C must be stated, so that it can be seen how many at-risk family members have attended clinic (A = C/N, where A is attendance at clinic).
The proportion of family members (A) who have attended clinic (and their whereabouts on the pedigree) gives some indication as to the spread of information around the family. The 'unknowns' are those who have not come forward to clinic, and therefore might not know about the availability of testing. These are potential future patients (F), and cannot be discounted unless they have actively declined counselling and testing. It is questionable as to whether non-response to an invitation to participate in an education/testing research programme counts as informed non-utilization. 'A' cannot be measured in studies involving active recruitment to a research testing protocol, and Ui has less meaning in these studies, as it only shows the participation level in the study, unless testing in that area is available solely as part of a research protocol.
Who is eligible for pre-symptomatic testing? The definition of the denominator includes more clauses and sub-clauses than any other part of the equation. It may be simplest to count everybody in the bloodline of the family. However, it is not usual practice to test those under the age of 18 years, or those unable to give informed consent due to mental health or learning problems. In a National Health System setting, when calculating the uptake amongst patients of one particular clinic (Uc), the family members resident in another region or country become ineligible for testing by that clinic.
It is unnecessary to test the children (and grandchildren) of anybody found to be a non-carrier. This reinforces the importance of including a time component in the calculation, as the number of people in the denominator is dynamic and may be reduced or increased by mutation-negative or mutation-positive results respectively.
Some descendants of a mutation-negative individual may have been counselled by a clinic prior to reduction of their risk. They must therefore be removed from the updated calculation of uptake with respect to counselling (C). Conversely, it is not usual to test children without having already tested the parent. Therefore, theoretically, until the parent has had a test, the children are 'ineligible'. If this is formally phrased, it could be said that only those at 50% risk of having inherited the mutation were 'eligible' for inclusion in the denominator, at any point in time.
This definition is too narrow because there may be an intervening relative who is unavailable for testing (probably deceased). As mutations in the BRCA1/2 genes are not fully penetrant, the children of an unaffected woman are still at risk of having inherited the faulty gene copy. So, the group of people who could be tested includes those in each vertical bloodline at most risk of inheriting the mutation, i.e. those at 50% risk, or those at 25% (or 12.5%) risk where the intervening generation is unavailable for testing.
And finally, any obligate carriers (usually alive and well parents of the affected proband in whom the mutation was found) could be said to be ineligible for inclusion in the denominator of an uptake calculation, as their status is known by default.
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