This study is sponsored by the Peter MacCallum Cancer Centre and was approved by the Peter MacCallum Human Research Ethics Committee (HREC/78093/PMCC-2021) on 22 December 2021. Site governance authorisation was granted on 7 February 2022 for the Peter MacCallum Cancer Centre and on 7 October 2022 for the Royal Melbourne Hospital, with a Clinical Trial Research Agreement executed between the sponsor and Melbourne Health.
Research aims
This hybrid type II effectiveness-implementation randomised clinical trial includes two aims:
- Assess the effectiveness of using the GPRI, relative to usual care, in improving patient outcomes including empowerment (primary outcome) after genetic counselling and testing for an inherited cancer predisposition; and
- Assess the implementation of the GPRI in genetic counselling appointments in terms of cost effectiveness, fidelity, penetration, and sustainability.
Setting
This research will be conducted at the PFCC, the conjoint clinical genetics service at the Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, located in Victoria, Australia. Patients are referred to the PFCC for a risk assessment based on personal and/or family history of cancer. Referrals are actioned by an intake assistant, with genetic counsellor oversight, who contacts the patient to obtain additional family history and/or clinical information. Once the intake process is complete, an appointment is booked with up to six weeks wait for the appointment date. Patients who are deemed at increased risk of an inherited predisposition to cancer and are likely to be offered genetic testing will typically attend two appointments: 1) a pre-test appointment during which consent for genetic testing is discussed and obtained; and 2) a results appointment at which the genetic test result is disclosed. The clinic is staffed by clinicians, comprising genetic counsellors, clinical geneticists, medical oncologists, gastroenterologists, and clinical genetics fellows.
Study design
A hybrid type 2 effectiveness-implementation trial has been designed to assess the effectiveness of using the GPRI in PFCC appointments while also assessing the implementation strategy (Table 1) (21).
Table 1
Hybrid Effectiveness-Implementation Trial Map
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Aims
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Framework
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Constructs
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Outcome
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Analysis level
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Measurement
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Data collection
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Effectiveness
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To assess the effectiveness of using the GPRI in genetic counselling
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FOCUS-GC
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Communication strategy
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Identify patient psychosocial needs during appointment
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Clinician
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No. of patient needs identified
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Appt. checklist, audio recording
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Address patient psychosocial needs during appointment
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Clinician
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Y/N patient needs address
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Process measures
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Appointment length
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Service
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Time (minutes)
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Appt. checklist, audio recording
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Referrals for support
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Clinician
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No. & type of referrals offered
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Appt. audio recording
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No. & type of referrals made
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Clinical data
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Letters to at-risk relatives
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Clinician
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No. letters written
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Clinical data
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Patient care experiences
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Satisfaction with appointment
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Patient
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Genetic Counselling Satisfaction Scale
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t3 & t6
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Patient changes
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Empowerment
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Patient
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Genetic counselling Outcome Scale
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-t1, t3 & t6
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Patient health
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Distress
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Patient
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Multidimensional Impact of Cancer Assessment Questionnaire
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t6
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Adaption
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Patient
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Psychological Adaption Scale
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t6 & t7
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Cancer risk management
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Patient
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Uptake of strategies
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t7
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Family changes
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Communication to at-risk relatives
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Patient
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No. of family members informed
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t7
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Implementation
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To assess the implementation of the GPRI in genetic counselling
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Implementation Outcomes Framework
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Acceptability
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Acceptable to implement GPRI in genetic counselling appts.
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Patient
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Acceptability patient survey
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Complete
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Clinician
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Acceptability staff survey
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Adoption
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Uptake by patient
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Patient
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GPRI pilot (early stage)
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Complete (uptake 94%)
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Uptake by clinician
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Clinician
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Use by clinician (Y/N)
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Appt. audio recording
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Feasibility
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Feasible to implement GPRI in genetic counselling
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Patient
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Feasibility patient survey
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Complete
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Clinician
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Feasibility staff survey
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Complete
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Feasibility of using GRPI routinely
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Structured interviews
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Fidelity
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GPRI implemented as intended
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Clinician
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Use by clinician (Y/N) and extent of use
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Appt. checklist, audio recording
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Implementation cost
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Health resource use
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Service
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Cost to service ($AUD)
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Health economic data
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Penetration
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Integration of GPRI in genetic counselling appointments
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Clinician
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No. of clinicians who use GPRI
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Appt. checklist, audio recording
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Sustainability
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Intention to routinely use GPRI
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Clinician
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Sustainability of using GPRI routinely
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Structured interviews
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The effectiveness of the GPRI will be tested using a randomised control trial (RCT) to assess outcomes of using the GPRI during PFCC appointments and will be guided by the Framework for Outcomes of Clinical commUnication Services for Genetic Counselling (FOCUS-GC) (22). Participants will be randomised to the control group (no GPRI) or the intervention group (GPRI). Patients in the control group will receive usual care consisting of the current standard of genetic counselling where the GPRI is not used. The intervention group participants will complete the GPRI within three days prior to both of their PFCC appointments for their clinicians’ use during these appointments.
Implementation of the GPRI will be concurrently assessed guided by Proctor’s Implementation Outcomes Framework (23). The cost-effectiveness, adoption, feasibility, fidelity, penetration, and sustainability will be assessed from the perspective of clinicians and the healthcare service.
Primary outcome
The primary outcome of patient empowerment, as measured by the Genetic Counselling Outcome Scale (GCOS-24), is measured from baseline to the primary timepoint of two weeks after the second PFCC appointment. The GCOS-24 is validated to measure change in patient empowerment from pre- to post-genetic counselling and consists of 24 items each with a 7-point Likert scale response option scored from 1 “strongly disagree” to 7 “strongly agree” (24). Negatively worded responses options are transformed so that all increases in scores represent an increase in empowerment and the total score is calculated by determining the sum of the scores (24).
Secondary outcomes
The effectiveness of using the GPRI, relative to usual care, will be further explored through secondary outcomes including change in GCOS-24 score from baseline to two weeks after the first PFCC appointment and proportion of respondents who meet the Minimum Clinically Important Difference (MCID) whose GCOS-24 score changes ≥10 points from baseline to two weeks after the second PFCC appointment (25). Other secondary outcomes include patient satisfaction at two weeks after first and second PFCC appointments, patient adaptation two weeks and six months after the second PFCC appointment, and impact of genetic test result two weeks after the second PFCC appointment. Uptake of cancer risk management strategies and communication of genetic information to at-risk family members will be assessed at six months after the second PFCC appointment. The proportion of psychosocial needs identified by clinicians during the PFCC appointments, support offered after the PFCC appointments, and duration of the PFCC appointments will be established. Implementation outcomes including cost-effectiveness, adoption (uptake of the GPRI by clinicians during appointments), fidelity (use of GPRI and extent of use by clinicians during appointments), penetration (number of clinicians who use the GPRI during appointments), and clinicians’ perceptions of the feasibility and sustainability of using the GPRI routinely will also be assessed.
Participants
Patients
This study will invite patients who are at increased risk of an inherited predisposition to cancer and are attending the PFCC for genetic testing. Patients attending their first appointment and who are likely to be offered genetic testing will be eligible. Involvement in this research is voluntary.
Eligibility
Patients will be considered eligible once their intake process is complete and their PFCC appointment has been booked. Inclusion in the study will be assessed by the research team, with input from the clinical team, based on the following criteria:
- Aged 18 years or older;
- Literate in English;
- Reasonable internet access and capacity to complete computer-based surveys; and
- Likely to be offered a genetic test during their first appointment.
Patients will be excluded if they have a known cognitive impairment or are eligible for the PRiMo study (Using Polygenic Risk Modification to improve breast cancer prevention; HREC no. HREC/64060/PMCC; ANZCTR: ACTRN12621000009819). Patients will become ineligible to participate if they do not consent to genetic testing during their first appointment.
Clinicians
Potential participating clinicians must be employed by the PFCC at the Peter MacCallum Cancer Centre or the Royal Melbourne Hospital and involved in providing genetic counselling and testing to patients. Potential participating clinicians include associate and certified genetic counsellors, clinical geneticists, clinical genetic fellows, medical oncologists, and gastroenterologists.
Recruitment
Patients
Recruitment will occur alongside standard PFCC clinical processes from May 2022 to December 2024, inclusive. Recruitment lists will be generated by reviewing the schedule for upcoming PFCC appointments and screening against the eligibility criteria. Eligible patients will be emailed a study invitation. It is estimated based on the response rate of a similar genetic counselling intervention study that approximately 50% of invited patients will agree to participate (18). Therefore, an estimated 702 potential participants will be invited to participate to achieve the requisite sample size.
The study database will be hosted on REDCap at the Peter MacCallum Cancer Centre (26, 27) and will house the Participant Information Statement, an e-consent framework, the GPRI, and all data collection instruments.
Randomisation
Randomisation of eligible patients to the intervention or control group will be conducted using randomly permuted blocks of varying sizes in a 1:1 ratio, stratified by sex and cancer status (affected or unaffected by cancer). The randomisation list will be computer-generated by an independent statistician and carried out centrally to ensure concealment. The study statistician will remain blinded until the database is cleaned, locked and ready for unblinding. The statistical analysis plan will be written and published on our centre’s website while blind to group allocation. Blinding of patient and clinicians to the allocation status will not be possible due to the nature of the intervention. Participants who are randomised into the intervention group will be emailed a link to the GPRI hosted on REDCap three days prior to each genetics appointment. The GPRI score will be automatically calculated using the REDCap auto-scoring capability and the completed measure and score will be emailed to the relevant clinician.
Clinicians
All eligible PFCC staff will be invited to a short (30 minute) study education session which will include training on how to use the GPRI. To participate in the study, clinicians agree to use the GPRI in appointments according to their clinical discretion with intervention group patients, and for all patients enrolled in the trial, audio-record the appointments and complete the post-appointment clinician checklist. Participating clinicians will also be invited to take part in a structured interview with a member of the research team.
Data collection
Patient-administered measures
Participants will complete four questionnaires during the intervention phase (Figure 1). After consenting, participants will complete the baseline questionnaire consisting of demographics and the GCOS-24. Two weeks after the first PFCC appointment, participants complete the second questionnaire including the GCOS-24 and the Genetic Counselling Satisfaction Scale (GCSS) (28). Two weeks after the second PFCC appointment, participants complete the third questionnaire including the GCOS-24, the GCSS, the Multidimensional Impact of Cancer Risk Assessment (MICRA) (29), and the Psychological Adaptation Scale (PAS) (30). Six months after the second PFCC appointment, participants complete the fourth questionnaire including the PAS, and purpose-designed items examining uptake of cancer risk management strategies and communication of genetic information to at-risk family members.
Clinical data
Clinical data (e.g., genetic testing results, the number and type of referrals for psychosocial support, letters written for at-risk family members, referrals for risk management) will be collected at various time points during the study from Epic, an electronic health records system, used at the Peter MacCallum Cancer Centre and the Royal Melbourne Hospital.
Clinician data
Clinician checklist
After each appointment, clinicians will be asked to complete a checklist that is comprised of items that mirror the GPRI domains. Clinicians will complete this electronic case report form (eCRF) to report whether each psychosocial need was discussed (yes/no) or not applicable.
Structured interviews
Clinicians will be asked to complete a structured interview during the post-intervention phase of the study about their experiences of using the GPRI and the feasibility and sustainability of routine use after the conclusion of the trial. Interviews will be audio-recorded with verbal consent from the clinician at the beginning of the interview. The interviews will follow a structured guide comprising two sections: 1) demographics and 2) feasibility and sustainability of using the GRPI in routine practice. The demographics section will include profession, number of years practicing and estimated number of times using the GPRI. Section two will include questions to explore: the clinician’s experiences of using the GPRI during appointments and whether they believe the GPRI to be a feasible and sustainable tool to use as part of routine care.
Healthcare resource use
A cost analysis comparing the intervention and control groups will be conducted from both a societal and public healthcare system perspective, using a bottom-up micro-costing approach. Clinicians will be asked to enter data pertaining to the time spent (in minutes) on administrative and clinical tasks for patients involved in the study. Clinicians will be asked to enter this data for 50 patients enrolled during the first 6-12 months of the intervention period and for 50 patients in the final 6-12 months. This will prevent over-burdening clinicians with data entry tasks and will allow analysis of the impact of gain of experience in using the GPRI.
Appointment data
Clinicians will be supplied with Dictaphones and asked to audio-record each appointment. Consent will be implied for clinicians through the opt in process and signing the delegation log and obtained from participants as part of their consent to take part in the overall study. At the end of each clinic, a member of the research team will collect the Dictaphones and transfer the audio-recording onto the PFCC network drive. A member of the research team will listen to each appointment audio-recording and, using a checklist, will record the frequency that psychosocial concerns included in the GPRI were discussed and whether psychosocial supports were offered. During the appointments where the GPRI was available, the audio-recording will be reviewed to examine the adoption by clinicians of the GPRI during appointment, whether the GPRI was used as intended to assess fidelity, and the integration of the GPRI results in the appointment to examine penetration. The member of the research team involved in this aspect of study will not be associated with the clinician team to preserve clinician anonymity. The audio-recordings will also be used to determine the length of each appointment.
Health economic data
Clinical data, patient-reported data, appointment data and clinician data will be collated and used for the health economic analysis. Only costs directly related to the study intervention/genetic condition will be considered. The cost per patient will be established by (1) identification of relevant clinical pathways in consultation with study investigators, (2) estimate resource measurement for each pathway, (3) estimate the unit cost for each resource, and lastly (4) apply the cost of resources to each clinical pathway. The cost of staff time will be based on time spent and the relevant gross salary award adjusted for on-costs (leave, leave-loading). Productivity costs (work absences, lost income), out-of-pocket and indirect patient costs will be estimated using patient data collected through the clinical questionnaires.
Data analysis
Sample size
A total sample size of 246 participants, 123 per group is required for 90% power to demonstrate that GPRI superior to usual care with a two-sided 5% significance level. This sample size is based on the following assumptions: a clinically meaningful absolute treatment difference in mean change in GCOS-24 scores from baseline to two weeks after the second PFCC appointment of 10 units in favour of GPRI (increase) (25), standard deviation (SD) of 20 units equal in each group and at each time point (baseline, two weeks after first PFCC appointment, and two weeks after second PFCC appointment) (25), and conservatively no correlation between baseline and repeated measures of GCOS-24 scores. Attrition is estimated to be similar to another genetic counselling intervention study where approximately 30% participant attrition was observed (31).
Statistical analysis
The biostatistician will devise a formal detailed statistical analysis plan for the study prior to unblinding. The analysis set will consist of all participants who were randomised, with all participants reported and analysed according to their randomised study arm.
Primary outcome
Primary outcome GCOS-24 scores will be analysed using a constrained longitudinal data analysis (cLDA) (32) model assuming a common mean across groups at baseline and a different mean for each group at each follow-up time point. The response will consist of all GCOS-24 scores (scores at baseline, and at two weeks after the first PFCC appointment and two weeks after the second PFCC appointment) and the model will include a random intercept for clinician and an unstructured variance-covariance matrix for the individual’s repeated measurements, factors representing treatment, time (categorical), and treatment-by-time interaction, and the stratification factors sex and cancer status at baseline, and will be further adjusted for cancer type. The mean change in GCOS-24 scores from baseline to each follow-up time point between the intervention group compared to the control group will be obtained. The primary hypothesis will be evaluated by obtaining the estimated difference between intervention and control groups in mean change in GCOS-24 score from baseline to two weeks after the second PFCC appointment, a two-sided 95% confidence interval and a p-value. This model provides valid inference in the presence of missing data if the data are missing at random. An analysis will be conducted using the delta-adjustment method under the pattern-mixture modelling framework in the context of multiple imputation to assess sensitivity to missingness not at random.
Secondary outcomes
In addition to the primary analysis of the GCOS-24 score, responders (defined as change from baseline to 2 weeks after second PFCC appointment in GCOS score ≥ 10) will be analysed using a logistic regression model using generalized estimating equations (GEEs) with an exchangeable correlation structure and robust standard errors for clustering by clinicians (33). Continuous secondary outcomes with repeated measures – satisfaction with genetic counselling and adaptation to genetic risk – will be analysed using a linear mixed-effects model. The model will include a random intercept for clinician and an unstructured variance-covariance matrix for the individual’s repeated measurements and factors representing treatment, time (categorical), and treatment-by-time interaction. Other secondary outcomes, impact of genetic test result and duration of PFCC appointments will be analysed using linear regression, total number of psychosocial needs identified in each appointment will be analysed using Poisson regression, and support offered to patients after appointments will be analysed using logistic regression. All these models will be fitted using GEEs with an exchangeable correlation structure and robust standard errors for clustering by clinicians and will be adjusted for the stratification factors sex and cancer status, with further adjustment for cancer type. These models provide valid inference in the presence of missing data if the data are missing completely at random (MCAR). Sensitivity analyses will be conducted using multiple imputation to explore the impact of any deviations from MCAR on the results.
Subgroup analyses for the comparison of the primary outcome, patient empowerment measured using the GCOS-24 score, for participants in the intervention group compared to the control group will be conducted by the stratification factors sex, cancer status (affected vs unaffected) and additionally by type of clinician (genetic counsellors vs doctors), including subgroup and an interaction term between treatment and subgroup in the model. All analyses of secondary outcomes and subgroups are exploratory and therefore require no adjustment for multiple testing. All statistical analyses will be conducted using Stata statistical software (34).
Health economic analysis
Resources will be itemised and valued in 2020 Australian Dollars (AUD). A cost analysis comparing control and intervention groups will be conducted from both a societal and public healthcare system perspective, using a bottom-up micro-costing approach. Costs will be compared using mean estimates, or through nonparametric bootstrap in the event of skewed data.
Data management, retention, and storage
All electronic data will be stored in REDCap. Data exported from REDCap during analyses will be stored in a secure folder on the internal network drive. All electronic files will only be accessible to the investigator team. Audio recordings of the appointments and the structured interviews will be deleted from the Dictaphone after transfer to the network drive.
All files and data relating to this project will be kept for a minimum of five years in accordance with the guidelines stipulated by the National Health & Medical Research Council in the Australian Code for the Responsible Conduct of Research. After this time, electronic data will be permanently deleted.
Ethical considerations and risk mitigation
The study will be conducted according to the NHMRC National Statement on Ethical Conduct in Human Research 2007 (and updates), and the World Medical Association Declaration of Helsinki 2013.
Management of distress
This study is not expected to detract from the usual standard of care for patients, as the GPRI has been validated to detect psychosocial needs in the clinical genetics setting and enhance communication between staff and patients. Any patients who experience distress during an appointment are counselled about the issues causing their distress during the appointment, relevant supports are identified, and referrals are made to appropriate psychological support services, if required. If a staff member identifies a participant is distressed based on their GPRI results, they will follow these standard clinical processes.
This study is not expected to cause any distress to clinical staff who participate or to members of the research team. However, if a staff member is distressed due to the completion of the staff questionnaire, they will be provided with support by the Director of the PFCC.
Dissemination of findings
The progress of the study and the study findings at completion will be communicated locally and internationally. Results will also be published in peer-reviewed journals and disseminated to genetic and oncology health professionals and researchers at national and international conferences.