Mackenzie's Mission: The Australian Reproductive Carrier Screening Project

Not Applicable

Active, not recruiting

• Conditions: X-Linked Genetic Diseases; Autosomal Recessive Disorder
• Interventions: Other: Reproductive Genetic Carrier Screening

• Registration Number: NCT04157595
• Lead Sponsor: Murdoch Childrens Research Institute

Brief Summary

This study will investigate reproductive genetic carrier screening (RGCS) in 10,000 couples across Australia. Carrier screening for approximately 1300 genes associated with severe, childhood-onset, X-linked and autosomal recessive conditions will be performed on each member of the couple. A combined result will be issued indicating whether the couple has a 'low' or 'increased' risk of having a child with a genetic condition. It is anticipated that 1-2% of couples will be at an increased risk of having an affected child.

The study will evaluate all aspects of the RGCS program to assess the feasibility and acceptability of a publicly-funded population-wide RGCS program, including:

* education of recruiting healthcare providers

* education of participating couples

* implementation and uptake of RGCS

* frequency of increased-risk couples and their reproductive decisions

* psychosocial impacts

* ethical issues

* health economic implications

* health implementation research

Detailed Description

PROTOCOL SYNOPSIS

Couples will be invited to take part in the study by their healthcare provider (HCP). The couple will enrol via an online portal, complete an education module, provide consent and complete a questionnaire. Those who consent to carrier screening will be sent mouth swab kits with samples returned by mail.The carrier screening performed will be done via accredited testing laboratories in partnership with clinical genetics services. Genetic counselling will be available to study participants throughout the process. Couples at increased risk will be offered a genetic counselling consultation and offered support to access reproductive options (i.e. prenatal diagnosis, preimplantation genetic diagnosis (PGD) which will be funded by the study for one cycle of IVF with PGD). All participants will be asked to complete an initial survey at study enrolment and invited to complete optional surveys at the time of screening, after return of screening results, and approximately 13 to 19 months after results. Subsets of participants will also be invited to take part in interviews.

GENE LIST FOR CARRIER SCREENING

The approximately 1300 genes tested in the Mackenzie's Mission carrier screening panel meet the following criteria:

1. The associated condition is one where an 'average' couple would take steps to prevent the birth of a child with that condition.

- This includes conditions with significant negative impact on quality of life for the child, the condition being lethal in childhood, and a significant impact on the family.

2. AND/OR: There is a potential benefit for knowing about the condition to inform management in the neonatal period. This criterion was particularly important if the condition was either not included on a newborn screening panel, and/or intervention would be required prior to results from newborn screening being known.

3. AND there is strong evidence for mutations in the gene being causative of the condition in question, with enough variants reported to allow confidence in informing couples of their chance of having a child with the condition in question.

Study Timeline

• Study First Submitted: 2019-10-21
• Study First Submitted QC: 2019-11-06
• Study First Posted: 2019-11-08
• Study Start: 2019-11-21
• Primary Completion: 2022-03-31
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-07
• Last Update Posted: 2024-04-09
• Study Completion: 2024-12-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 18302

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Participating Couples	Reproductive Genetic Carrier Screening	Reproductive Genetic Carrier Screening

Primary Outcome Measures

Name	Time	Method
Reproductive Choices made by Increased-Risk Couples	Reproductive choices made by couples will be tracked from the date an increased-risk result is received until study closure on 31 December 2022. A subset of couples will be interviewed ~19 months after receiving an increased-risk result.	For pregnant couples, the investigators will ascertain how many have prenatal diagnosis (PND), and of those who have PND and an affected fetus is identified, how many terminate the pregnancy. For those who are not pregnant at the time of screening, the investigators will ascertain choices for future pregnancies that occur during the timeframe of the study, including how many choose preimplantation genetic diagnosis (PGD), how many choose a naturally conceived pregnancy with PND and how many choose a naturally conceived pregnancy without any testing.
Screening Uptake (Quantitative)	At offer of screening	Practitioners offering screening will be asked to record the number of couples offered screening which will allow calculation of screening uptake.
Frequency of Increased-Risk Couples	At reporting of results (~Weeks 5-6 since enrolment)	Analysis of carrier frequencies of the genes tested and the frequency of identification of increased-risk couples
Cohort Characteristics of those who decline and those who accept RGCS	Couples who decline screening;at offer or at enrolment (Day 0); optional. Couples who accept screening; at enrolment (Day 0); compulsory.	Short survey capturing personal information: age, country of birth, language spoken at home, ethnicity, religion and religiosity, education level, employment status, household income, marital status, pregnancy history and family/genetic history information.
Predictors of Uptake - Decliners	At decision not to provide samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional	Survey asking main reason(s) for declining to participate informed by the Health Belief Model (HBM). The HBM is used to predict and explain uptake of a health behaviour. It includes four components: perceived benefits, perceived susceptibility, perceived severity and perceived barriers (Janz and Becker 1984). A subset of declining couples will be invited for interview to explore the decision-making process and their reasons for declining testing.
Predictors of Uptake - Acceptors	At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional	Survey asking main reason(s) for choosing to participate informed by the Health Belief Model (HBM). The HBM is used to predict and explain uptake of a health behaviour. It includes four components: perceived benefits, perceived susceptibility, perceived severity and perceived barriers (Janz and Becker 1984)

Secondary Outcome Measures

Name	Time	Method
Participant Experience - State-Anxiety - pre-screening II	At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional	Six-item short-form of the state-anxiety scale of the Spielberger State-Trait Anxiety Inventory (STAI) (Marteau and Bekker 1992). This scale measures how the respondent feels "right now, at this moment". Scores range from 20 to 80. A high score indicates the presence of high levels of anxiety.
Participant Experience - State-Anxiety - post-result	Low-risk and increased-risk couples; post-result (~Weeks 17-18 since enrolment); optional	Six-item short-form of the state-anxiety scale of the Spielberger State-Trait Anxiety Inventory (STAI) (Marteau and Bekker 1992). This scale measures how the respondent feels "right now, at this moment". Scores range from 20 to 80. A high score indicates the presence of high levels of anxiety.
Participant Experience - State-Anxiety - long-term follow-up	Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional	Six-item short-form of the state-anxiety scale of the Spielberger State-Trait Anxiety Inventory (STAI) (Marteau and Bekker 1992). This scale measures how the respondent feels "right now, at this moment". Scores range from 20 to 80. A high score indicates the presence of high levels of anxiety.
Participant Experience - Trait-Anxiety - post-result	Low-risk and increased-risk couples; post-result (~Weeks 17-18 since enrolment); optional	20-item trait-anxiety scale (Form Y2) of the Spielberger State-Trait Anxiety Inventory (STAI). This scale measures how the respondent "generally" feels. Scores range from 20 to 80. A high score indicates the presence of high levels of anxiety.
Participant Experience - Trait-Anxiety - long-term follow-up	Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional	20-item trait-anxiety scale (Form Y2) of the Spielberger State-Trait Anxiety Inventory (STAI). This scale measures how the respondent "generally" feels. Scores range from 20 to 80. A high score indicates the presence of high levels of anxiety.
Health Economic Impact - Assessment of Quality of Life - post-result	Low-risk and increased-risk couples; post-result (~Weeks 17-18 since enrolment); optional	12-item Assessment of Quality of Life-4D (AQoL-4D) questionnaire (Hawthorne, Richardson and Osbourne 1999; Richardson and Hawthorne 1998). This questionnaire measures health-related quality of life in four dimensions: Independent Living, Relationships, Mental Health and Senses. Total scores range from a minimum of 12 to a maximum of 48. Higher scores indicate a lower health-related quality of life.
Health Economic Impact - Assessment of Quality of Life - long-term follow-up	Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional	12-item Assessment of Quality of Life-4D (AQoL-4D) questionnaire (Hawthorne, Richardson and Osbourne 1999; Richardson and Hawthorne 1998). This questionnaire measures health-related quality of life in four dimensions: Independent Living, Relationships, Mental Health and Senses. Total scores range from a minimum of 12 to a maximum of 48. Higher scores indicate a lower health-related quality of life.
Participant Experience - Attitudes/Perceptions	Couples who decline screening;at offer or at enrolment (Day 0); optional. Couples who accept screening; at enrolment (Day 0); compulsory.	Survey assessing attitudes towards carrier screening in the general population, and the attitudes of the couple towards carrier screening for themselves.
Participant Experience - Trait-Anxiety - pre-screening	Couples who decline screening; at enrolment (Day 0); optional. Couples who accept screening; at enrolment (Day 0); compulsory.	20-item trait-anxiety scale (Form Y2) of the Spielberger State-Trait Anxiety Inventory (STAI). This scale measures how the respondent "generally" feels. Scores range from 20 to 80. A high score indicates the presence of high levels of anxiety.
Participant Experience - Trait-Anxiety - pre-screening II	At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional	20-item trait-anxiety scale (Form Y2) of the Spielberger State-Trait Anxiety Inventory (STAI). This scale measures how the respondent "generally" feels. Scores range from 20 to 80. A high score indicates the presence of high levels of anxiety.
Health Economic Impact - Assessment of Quality of Life - pre-screening	Couples who decline testing, at enrolment (Day 0); optional. Couples who accept testing, at enrolment (Day 0); compulsory	12-item Assessment of Quality of Life-4D (AQoL-4D) questionnaire (Hawthorne, Richardson and Osbourne 1999; Richardson and Hawthorne 1998). This questionnaire measures health-related quality of life in four dimensions: Independent Living, Relationships, Mental Health and Senses. Total scores range from a minimum of 12 to a maximum of 48. Higher scores indicate a lower health-related quality of life.
Participant Experience - State-Anxiety - pre-screening	Couples who decline screening; at enrolment (Day 0); optional. Couples who accept screening; at enrolment (Day 0); compulsory.	Six-item short-form of the state-anxiety scale of the Spielberger State-Trait Anxiety Inventory (STAI) (Marteau and Bekker 1992). This scale measures how the respondent feels "right now, at this moment". Scores range from 20 to 80. A high score indicates the presence of high levels of anxiety.
Participant Experience - Decisional Conflict	At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional	16-item scale measuring personal perception of uncertainty, factors contributing to uncertainty, and effective decision making. Includes five subscores: uncertainty, informed, values clarity, support, effective decision making (O'Conner 1993 (updated 2010)). Total scores range from 0 \[no decisional conflict\] to 100 \[very high decisional conflict\].
Participant Experience - Genomics Outcome Scale (GOS-6)	Increased-risk couples, before and after genetic counselling session (~Weeks 5-6 since enrolment)	6-item scale measuring empowerment as an outcome of clinical genetics services. Total scores range from a minimum of 6 to a maximum of 30. Higher scores indicate higher levels of empowerment (Grant et al. 2018)
Participant Experience - Evaluation of Educational and Decision-Aid Materials	At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional	Questions to evaluate resources developed for participating couples e.g. decision aid, website, brochure
Participant Experience - Decisional Regret - long-term follow-up	Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional	A 5-item scale measuring distress and remorse after a health care decision. Scores range from 0 \[no regret\] to 100 \[high regret\]. Subset of low-risk couples to be contacted for interview to explore experience of having testing and receiving a low-risk result.
Health Economic Impact - Participants' willingness to pay	Couples who decline screening, at enrolment (Day 0); optional. Couples who accept screening, at enrolment (Day 0); compulsory	Questions with randomised monetary values to assess maximum amount participants would be willing to pay, and whether the test should be government, privately or Medicare funded.
Participant Experience - Deliberation	At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional	6-item scale measuring decision deliberation. Dichotomous scale: responses below the midpoint (11 or under) classified as not deliberated and those at or above the midpoint as deliberated (Van den Berg, Timmermans, Ten et al 2006)
Participant Experience - Decision-Making Approach	At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional	Survey evaluating decision-making approach i.e. whether it was an individual or shared decision and who was involved in the decision-making process, e.g. couples, family, health-professional
Participant Experience - Qualitative Interviews	Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional	Subset of low-risk couples to be contacted for interview to explore longer-term experience of having testing and receiving a low-risk result. Subset of increased-risk couples to be contacted for interview to explore the experience of receiving a increased-risk result, the use of this information in reproductive decision-making, and the communication of genetic information within families.
Participant Experience - Health Literacy	At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional	Questions to assess health literacy level
Participant Experience - Decisional Regret - post-result	Low-risk and increased-risk couples; post-result (~Weeks 17-18 since enrolment); optional	A 5-item scale measuring distress and remorse after a health care decision. Scores range from 0 \[no regret\] to 100 \[high regret\]. Subset of low-risk couples to be contacted for interview to explore experience of having testing and receiving a low-risk result.

Trial Locations

Locations (24)

Royal Hospital for Women; 🇦🇺 Sydney, New South Wales, Australia

Royal Prince Alfred Hospital; 🇦🇺 Sydney, New South Wales, Australia

Sydney Children's Hospital, Randwick; 🇦🇺 Sydney, New South Wales, Australia

Westmead Hospital; 🇦🇺 Sydney, New South Wales, Australia

Women's and Children's Hospital; 🇦🇺 Adelaide, South Australia, Australia

Joondalup Health Campus; 🇦🇺 Joondalup, Western Australia, Australia

Wagga Wagga Base Hospital; 🇦🇺 Wagga Wagga, New South Wales, Australia

King Edward Memorial Hospital; 🇦🇺 Perth, Western Australia, Australia

Campbelltown Hospital; 🇦🇺 Sydney, New South Wales, Australia

Liverpool Hospital; 🇦🇺 Liverpool, New South Wales, Australia

The Children's Hospital at Westmead; 🇦🇺 Sydney, New South Wales, Australia

Tamworth Communith Health Services; 🇦🇺 Tamworth, New South Wales, Australia

Taree Community Health Service; 🇦🇺 Taree, New South Wales, Australia

Victorian Clinical Genetics Services; 🇦🇺 Melbourne, Victoria, Australia

Northern Hospital; 🇦🇺 Melbourne, Victoria, Australia

Royal Brisbane and Women's Hospital; 🇦🇺 Brisbane, Queensland, Australia

Cairns Hospital; 🇦🇺 Cairns, Queensland, Australia

Mareeba Hospital; 🇦🇺 Mareeba, Queensland, Australia

Hunter Genetics; 🇦🇺 Newcastle, New South Wales, Australia

Forster Community Health Service; 🇦🇺 Forster, New South Wales, Australia

West Gippsland Heath Service (Warragul Hospital); 🇦🇺 Warragul, Victoria, Australia

Royal Hobart Hospital; 🇦🇺 Hobart, Tasmania, Australia

Mercy Hospital for Women; 🇦🇺 Melbourne, Victoria, Australia

Royal Darwin Hospital; 🇦🇺 Darwin, Northern Territory, Australia