Reaching detection targets in familial hypercholesterolaemia: Comparison of identification strategies.

TL;DR: Child-parent Cascade Screening is the fastest strategy for identifying FH in the population and is applicable to any country to close the FH detection gap.

About: This article is published in Atherosclerosis.The article was published on 2020-01-01 and is currently open access. It has received 26 citations till now. The article focuses on the topics: Population.

Summary

Introduction

• 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. [1].
• 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.

Cascade Testing

• 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.

Child-parent Screening

• 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. [10].
• 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.
• Office for National Statistics (2017) data were used for population size [12], fertility rate [13], maternal age distribution [10] and the number of deaths per year [14] and WHO/UNICEF data for immunization coverage. [15].
• 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.

Results

• 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.

Discussion

• 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 [19] is likely to be high because it assumed a lower rate of FH identification for Child-parent Screening than was observed in practice.[8].
• 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:.

Figure Legend

• 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.

Figures

Table 1: Sensitivity analysis for time to identify different proportions of FH cases in the UK population using the three FH identification strategies.

Table 2: Time to identify different proportions of FH cases by Child-parent Cascade Screening according to population where initial identification levels are known.

Frequently asked questions

Q1. What have the authors contributed in "Reaching detection targets in familial hypercholesterolaemia; comparison of identification strategies" ?

In this paper, the authors developed a model to estimate the time to identify different proportions of FH in the population for the three identification strategies. 

Q2. What data were used for population size?

Office for National Statistics (2017) data were used for population size [12], fertility rate [13], maternal age distribution [10] and the number of deaths per year [14] and WHO/UNICEF data for immunization coverage. [15] 

Q3. How many cases of FH can be identified by child-parent screening?

Child-parent Cascade Screening could identify 50% of all FH cases in about 17 years and 75% detection in about 30 years, after which most affected families would be known and Cascade Testing would continue as the main and highly cost-effective identification method. 

Q4. How long can a method be sustained to identify a steady number of unrelated cases?

The method is self-limiting and can only be sustained if supported by a separate method to provide a steady and substantial number of unrelated index cases. [7] 

Q5. How many years would it take to identify all FH cases?

Based on the current efficacy of Cascade Testing (number of new per known cases identified), 5098 unrelated FH index cases would need to be found each year for Cascade Testing to reach the 25% target in 5 years. 

Q6. How long would it take to identify all FH cases?

The current index case identification rate is 556 per year; doubling this to 1112 would still require 31 years to reach the 25% detection target. 

Q7. What is the fastest strategy for closing the identification gap in FH?

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. 

Q8. What is the benefit of screening children for FH?

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. 

Q9. What is the cost of Child-parent Cascade Screening?

Child-parent Cascade Screening is a strategy that has been shown to be effective and affordable, costing about £980 per new FH case identified. [9] 

Q10. What was the effect of doubling the efficacy of Cascade Testing?

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. 

Q11. What is the average age of a child at an NHS health check?

Electronic health records in adults are a potential supplement to identifying new FH index cases but largely miss the preventive opportunity (median age at an NHS Health Check is about 60 years). [22] 

Q12. What is the effect of the Cascade Screening on the child?

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.