Reaching detection targets in familial hypercholesterolaemia: Comparison of identification strategies.
Summary (3 min read)
- Familial hypercholesterolemia (FH) is a common and preventable cause of premature ischaemic heart disease (IHD).
- There are about 260,000 heterozygous affected individuals in the UK (prevalence 1 in 250) who have about a 100-fold excess risk of fatal myocardial infarction between ages 20 and 39 years. .
- A fatal or non-fatal IHD event affects about 50% of FH-positive men before age 50 and about 30% of FH-positive women by age 60. .
- How this would be delivered was not specified.
- The authors use publicly available data to compare the time to reach 25%, 50% and 75% identification for the UK, its home nations and other countries where estimates of FH identification have been recently reported.
- Supplementary Figure 1 gives the equation used to calculate the number of new FH individuals identified each year by Cascade Testing; the number of new FH relatives identified per known index FH mutation-confirmed case multiplied by the background number of new index FH cases identified each year from opportunistic/targeted testing (eg. high cholesterol level identified in an adult in primary care during a Health Check or in secondary care following a non-fatal cardiac event).
- The authors assumed that all new index cases are unrelated (or else they would identify each other) to provide a best-case estimate and that all available relatives are identified within a year of identifying an index case.
- In the model the authors reduced the number of new index cases identified per year in proportion to the population increase in FH detection each year.
- For Child-parent Screening a model was developed that avoids counting affected parents twice if more than one child in a family is identified as positive for FH.
- This applies from the 3rd year of screening onwards, because the average time between births in a family is 2 years. .
- The authors also avoided double-counting parents when a child, previously identified as positive, becomes a parent and has their own children screened.
- The equations for the first 2 years of screening and from the 3rd year onwards are shown in Supplementary Figure 2.
- The number (N) of 1-year old children (the age at screening) is the number of births per year and screening uptake (U) is the proportion attending for immunization at 1 year multiplied by the acceptance of the offer of screening among immunized children.
Child-parent Cascade Screening
- For Child-parent Cascade Screening each FH positive child also leads to the identification of their affected siblings (older siblings in the first two years of screening) and grandparent.
- Such FH-positive individuals are counted only once in the equations in Supplementary Figure 3 (i) for the first 2 years of screening and (ii) for the 3rd year of screening onwards, which are given separately because the impact of cascade testing is greater in the first two years of screening than subsequent years, when relatives may have already been identified or not yet borne.
- Office for National Statistics (2017) data were used for population size , fertility rate , maternal age distribution  and the number of deaths per year  and WHO/UNICEF data for immunization coverage. .
- Input data are summarised in Supplementary Table 1.
- Sensitivity analyses were performed to examine the effect of doubling the efficacy of Cascade Testing (number of new per known cases identified) and increasing the uptake of Child-parent Screening by 10% points.
- Figure 1 shows plots of FH identification for Cascade Testing, Child-parent Screening and Child-parent Cascade Screening in the UK.
- The results show that the 25% NHS identification target is reached after 47 years, 12 years and after 8 years respectively.
- The plots are curved, because the rate of identification declines with increasing proportions of all cases found for each strategy.
- Comparable plots for England, Scotland, Wales and Northern Ireland are given in Supplementary Figure 4.
- Table 2 gives the time to identify 25%, 50% and 75% of all FH cases by Child-parent Cascade Screening for 12 countries (including the 4 home nations of the UK) where current proportions of known FH have been reported.
- The results of this analysis show that the fastest strategy for closing the identification gap in FH is Child-parent Cascade Screening, an integration of universal screening in childhood, based on total cholesterol measurement supported by FH mutation testing during immunisation and subsequent Cascade Testing within mutation-positive families.
- The estimate for Child-parent Cascade Screening  is likely to be high because it assumed a lower rate of FH identification for Child-parent Screening than was observed in practice..
- Both child, and parent benefit from such screening, from life-style interventions and the timely introduction of drug therapy (principally statins); but the child benefits twice, once by reducing his/her own risk of premature ischaemic heart disease and again by avoiding the premature death of a parent.
- The authors projections are presented as the proportion of all cases of FH identified in the population, rather than in specified age groups, because identification targets are likely to be set for the whole population, as they have been in the UK.
- Conflicts of Interest: None Funding: None Acknowledgements:.
- Proportion of all FH cases in the UK identified over time for Cascade Testing, Childparent Screening and Child-parent Cascade Screening (integration of first two methods), also known as Figure 1.
- NHS 25% target denoted by horizontal dotted line.
- Supplementary Figure 1: Flowchart for estimating the number of FH cases identified each year by Cascade Testing Supplementary Figure 2: Flowchart for estimating the number of FH cases identified each year by Child-parent Screening Supplementary Figure 3: Flowchart for estimating the number of FH cases identified by Child-parent Cascade Screening (i):.
- In the 1st and 2nd years of Child-parent Cascade Screening (ii): Each year, in the 3rd year and onwards of Child-parent Cascade Screening Supplementary Figure 4: Time to detect proportions of all FH for England, Scotland, Wales, and Northern Ireland.
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