Exploring Perceptions of the Proposed Cystic Fibrosis Screening Protocol Incorporating Next Generation Sequencing

Health

Exploring Perceptions of the Proposed Cystic Fibrosis Screening Protocol Incorporating Next Generation Sequencing

Newborn bloodspot screening for cystic fibrosis (CF) became part of the national screening programme in 2007. Screening for CF is also well established internationally. The current algorithm works well, but has some disadvantages:

carrier reporting - which is not the intention of CF screening in the UK (~200 pa);
need for repeat samples which can be costly and contribute to parental worry (~300 pa.);
mutation panels do not fully reflect the ethnic diversity of the birth population;
identification of children designated as CF screen positive, inconclusive diagnosis (CFSPID) which can cause long-term uncertainty (~20-30 pa).

A trial of Next Generation Sequencing (NGS) in one centre found that it was technically feasible at a reasonable cost and with an acceptable turnaround time. In addition, the trial determined that using NGS could mitigate against some of the disadvantages described above, albeit with some reduction in test sensitivity.

A previous project has explored public attitudes towards this shift towards the use of NGS within CF Screening. This proposed work will complement this existing work by employing an integrated, mixed-methods approach through four work packages to explore the views of people affected by CF, in various ways, towards the potential changes to CF screening protocol.

Aims

a. What are the anticipated impacts on families and the NHS of avoiding or increasing the reporting of CFSPID cases?

b. How are trade-offs made and valued between ensuring that we do not miss any cases and potentially causing uncertainty (i.e. sensitivity vs specificity) and how is this viewed by different people and groups?

c. How is the proposal to use expanded genomic testing in the newborn screening programme for CF viewed by different people and groups?

d. What do people feel about not detecting and reporting carriers?

Methods

CF NGS employs an integrated, mixed-methods approach including:

interviews
focus groups
questionnaires
workshops (using Q-methodology)

Effective start/end date: 01/12/2021 - 28/02/2023

Work package 1:

This work package will address the questions from the project aims a, c & d:

a. What are the anticipated impacts on families and the NHS of avoiding or increasing the reporting of CFSPID cases?

c. How is the proposal to use expanded genomic testing in the newborn screening programme for CF viewed by different people and groups?

d. What do people feel about not detecting and reporting carriers?

This work package will deliver Project Deliverable 1: To gather, compare and analyse the views of a range of stakeholders on the proposed CF screening protocol incorporating NGS, including how this may be used in differing ways to include or avoid the identification of cases of CFSPID.

Work package 2:

This work package will address the questions from the project aims b, c & d:

c. How is the proposal to use expanded genomic testing in the newborn screening programme for CF viewed by different people and groups?

d. What do people feel about not detecting and reporting carriers?

This work package will deliver Project Deliverable 2: To use the outcomes to inform discussions and decisions by the FMCH group and UK NSC about the inclusion and use of the proposed protocol within CF newborn screening nationally.

It will also deliver Project Deliverable 3: To consider what generalisable information on the views of stakeholders on newborn screening could be generated from this exercise to inform other FMCH and UK NSC discussions, particularly involving the wider use of genomic testing as a part of newborn screening.

Work package 3:

This work package will address the questions from the project aims a, b, c & d:

a. What are the anticipated impacts on families and the NHS of avoiding or increasing the reporting of CFSPID cases?

c. How is the proposal to use expanded genomic testing in the newborn screening programme for CF viewed by different people and groups?

d. What do people feel about not detecting and reporting carriers?

This work package will deliver Project Deliverables 1, 2 & 3 (as above).

Work package 4:

This work package will address the questions from the project aims b & c:

c. How is the proposal to use expanded genomic testing in the newborn screening programme for CF viewed by different people and groups?

This work package will deliver Project Deliverable 4: To evaluate and learn from the exercise to inform future stakeholder engagement activities by the UK NSC and screening programmes. Plans and resources for evaluation will need to be built in from the beginning, and specialist expertise might be sought for this.

SURVEY FOR PROFESSIONALS:

We have devised an online survey for professionals who have any experience working with children and families with cystic fibrosis (e.g. doctors, nurses, clinical geneticists, genetic counsellors, screening midwives, social workers, dieticians, physiotherapists, newborn screening laboratory staff, school staff etc.,) that should take no more than 15-20 minutes to complete. The purpose of this is to explore views of professionals with respect to newborn bloodspot screening for cystic fibrosis and the potential for using more extensive gene sequencing in the protocol. Further information is available via the full Participant Information Sheet. We have also provided a short background and explanation to the study below (this is also available via the questionnaire/PIS links).

Background:

What will incorporating NGS into CF screening mean?

Incorporating NGS, will mean that the analysis is more comprehensive in terms of the number of gene mutations that are screened; all babies with an elevated IRT will be screened for more than 300 mutations compared with the 4-mutation panel, followed by (up to) 50-mutation panel currently used. Replacing these more limited panels seeks to achieve three main goals:

Avoiding reporting probable carriers (currently around 200 per annum)

Reducing the number of repeat IRT heel prick tests (currently around 300 per annum)

Ensuring that the mutations detected more adequately reflect the ethnic diversity in the population.

What did the NGS analysis trial tell us?

During the NGS analysis trial, involving 70,000 babies, variants of varying clinical consequence were given a score = 1 per allele, and those with clearly pathogenic mutations = 2 per allele.

It was found that:

Referring babies with a combined score of 3 (one pathogenic mutation combined with one mutation of varying clinical consequence – a sensitive approach), would:

Result in an increase (from 25 per annum to 80 per annum in the UK) in the designation of infants with ‘Cystic Fibrosis Screen Positive – Inconclusive Diagnosis’ (CFSPID)
Be likely to help avoid a small number of missed CF cases when compared with restricting reporting to those with a score of 4.

Referring babies with a combined score of 4 (or two clearly pathogenic mutations – a specific approach) would:

Result in a reduction (from 25 per annum to 5 per annum in the UK) in the designation of infants with ‘Cystic Fibrosis Screen Positive – Inconclusive Diagnosis’ (CFSPID)
Create a possible chance (less than 10 per annum) of those with true CF being missed at screening - the majority of these babies will be diagnosed clinically by the age of two years

We are interested to hear your views on the proposed CF screening protocol incorporating next generation sequencing (NGS). The information will inform discussions and decisions by the fetal, maternal and child health (FMCH) group and UK National Screening Committee (UK NSC) about the inclusion and use of the proposed protocol within CF newborn screening nationally.

Although the survey is anonymous, you are invited to provide your details via a separate link at the end, if you would like to find out more and/or be involved in the rest of the study.

Reports

Effective start/end date: 01/12/2021 - 28/02/2023

Work package 1:

This work package will address the questions from the project aims a, c & d:

a. What are the anticipated impacts on families and the NHS of avoiding or increasing the reporting of CFSPID cases?

c. How is the proposal to use expanded genomic testing in the newborn screening programme for CF viewed by different people and groups?

d. What do people feel about not detecting and reporting carriers?

Work package 2:

This work package will address the questions from the project aims b, c & d:

c. How is the proposal to use expanded genomic testing in the newborn screening programme for CF viewed by different people and groups?

d. What do people feel about not detecting and reporting carriers?

Work package 3:

This work package will address the questions from the project aims a, b, c & d:

a. What are the anticipated impacts on families and the NHS of avoiding or increasing the reporting of CFSPID cases?

c. How is the proposal to use expanded genomic testing in the newborn screening programme for CF viewed by different people and groups?

d. What do people feel about not detecting and reporting carriers?

This work package will deliver Project Deliverables 1, 2 & 3 (as above).

Work package 4:

This work package will address the questions from the project aims b & c:

c. How is the proposal to use expanded genomic testing in the newborn screening programme for CF viewed by different people and groups?

SURVEY FOR PROFESSIONALS:

Background:

What will incorporating NGS into CF screening mean?

Avoiding reporting probable carriers (currently around 200 per annum)

Reducing the number of repeat IRT heel prick tests (currently around 300 per annum)

Ensuring that the mutations detected more adequately reflect the ethnic diversity in the population.

What did the NGS analysis trial tell us?

During the NGS analysis trial, involving 70,000 babies, variants of varying clinical consequence were given a score = 1 per allele, and those with clearly pathogenic mutations = 2 per allele.

It was found that:

Referring babies with a combined score of 3 (one pathogenic mutation combined with one mutation of varying clinical consequence – a sensitive approach), would:

Result in an increase (from 25 per annum to 80 per annum in the UK) in the designation of infants with ‘Cystic Fibrosis Screen Positive – Inconclusive Diagnosis’ (CFSPID)
Be likely to help avoid a small number of missed CF cases when compared with restricting reporting to those with a score of 4.

Referring babies with a combined score of 4 (or two clearly pathogenic mutations – a specific approach) would:

Result in a reduction (from 25 per annum to 5 per annum in the UK) in the designation of infants with ‘Cystic Fibrosis Screen Positive – Inconclusive Diagnosis’ (CFSPID)
Create a possible chance (less than 10 per annum) of those with true CF being missed at screening - the majority of these babies will be diagnosed clinically by the age of two years

Although the survey is anonymous, you are invited to provide your details via a separate link at the end, if you would like to find out more and/or be involved in the rest of the study.