RhFFUS is a cohort study of children with non-specific mitral and/or aortic valve abnormalities detected on prior screening echocardiography. Children will be assessed prospectively for the development of progressive valve abnormalities and retrospectively for the incidence of ARF. The comparator will be age, gender, community and ethnicity-matched controls who have previously had a normal screening echocardiogram (see Figure
Figure 1 Protocol for selection of participants for RhFFUS. “Rural locations” comprise those communities involved in the gECHO that are outside of the cities of Cairns and Darwin. “Urban locations” comprise communities involved (more ...)
Participants in this study will comprise a subset of children who had an echocardiogram as part of the earlier gECHO screening study. These participants reside in 32 remote communities across northern and central Australia (see Figure
The 32 RhFFUS sites from Western Australia, the Northern Territory, and far north Queensland.
Children who participated in the gECHO study will be eligible for inclusion in RhFFUS if they identify as Aboriginal Australian and/or Torres Strait Islander and live in a remote location.
Children who participated in the gECHO study will not be eligible for inclusion in RhFFUS if they identify as non-Indigenous Australians, live in urban locations, had a diagnosis of definite RHD based on gECHO screening, or had a diagnosis of congenital valvular heart disease that may generate morphologic or functional abnormalities similar to RHD (bicuspid aortic valve, dilated aortic root, mitral valve prolapse).
Cases will be children with non-specific findings on their gECHO screening echocardiogram. More specifically, their screening echocardiogram from gECHO must not fulfill WHF echocardiography criteria for definite RHD
] and must meet one of the echocardiographic criteria outlined below. Given the uncertainty of interpretation of minor echocardiographic abnormalities, criteria for cases are more sensitive than WHF criteria for borderline RHD
]; 47 of the 137 cases included in RhFFUS satisfy the criteria for borderline RHD. Controls will be children who had a normal echocardiogram as outlined below.
1. One or more morphologic changes of the mitral valve (MV)* and/or aortic valve (AV)* without pathologic mitral regurgitation (MR)* or aortic regurgitation (AR)*; or
2. Pathologic MR* with no or one morphologic feature of RHD* or pathologic AR* with no or one morphologic feature of RHD* (not both); or
3. Multiple MR jets and/or multiple AR jets (in at least two views) that do not fulfill criteria for pathologic MR* or AR*
Note: *Criteria for morphologic changes of MV and AV, and pathologic AR and MR as described by WHF criteria
1. No morphologic features of RHD of the AV or MV; and
2. MR < 1 cm; and
3. No AR; and
4. No other acquired or congenital valvular heart disease
Note: *Criteria for morphologic changes of MV and AV, and pathologic AR and MR as described by WHF criteria
The matching process will involve stratifying all eligible gECHO participants by community, gender and age. For each identified case, the closest age-matched control from the same community and of the same gender will then be selected and assigned to the case. This process will be repeated so that two matched controls are assigned to each case.
Sample size estimations are based on projected rates of ARF based on the annual incidence of ARF in people with known RHD (2.5%) and the background annual incidence of ARF in 5 to 14 year old Aboriginal and Torres Strait Islander children in the NT (0.27%) (personal communication Northern Territory ARF/RHD register) over a five year period. Based on an assumed alpha of 0.05 and beta of 0.1 (power of 90%) detecting a difference of one or more episodes of ARF in 12.5% of cases and 1.35% of controls over five years of follow-up, and using a ratio of cases to controls of 1:2, would require a sample size of 83 cases and 165 controls or a total number of 248 reviews. While it is apparent that carditis in the acute setting of ARF may resolve in up to half of cases
] there are no clear data to inform the powering of progression of non-specific echocardiographic changes. Nonetheless, if it is assumed at most 5% of controls will develop morphologic and function valvular changes on echocardiography compared with 20% of those with pre-existing non-specific changes then it would require the follow-up of 77 cases and 154 controls to detect such a difference with the tolerances above, a number of enrolments well within the projected subject numbers.
Parents, carers or guardians of all identified subjects will be informed regarding the study using local Indigenous research staff and local language translators as required. Written informed consent will be obtained. In addition written assent will be obtained from subjects who are 14 years and older. Subjects who are 16 years and older, who fulfill the criteria for mature minors
] and who are not living with the people who would normally be identified as parents, carers or guardians will be able to provide their own consent.
Potential participants will be approached with the assistance of local research assistants and the local primary health care centre. In addition, RhFFUS staff will visit the homes of potential participants in the company of a local health care staff member or a community-based Indigenous Australian research assistant in order to contact and enroll potential participants. If potential cases have moved to another location since the gECHO project, attempts will be made to ascertain their most recent address and, if feasible, to contact and follow them up there.
Data collection and outcomes
Outcome data for cases and controls will include ARF incidence and the development or progression of mitral and/or aortic valve abnormalities.
(a) ARF incidence
The occurrence and timing of episodes of ARF will be assessed retrospectively for 5 years from the time of the RhFFUS screening echocardiography. Anecdotal evidence suggests that in the setting where RhFFUS is being conducted, episodes of ARF may be missed or not recorded owing to insufficient diagnostic information being collected at time of presentation to primary health care sites. Thus, in order to increase the power of RhFFUS to detect differences between case and controls, four categories of ARF will be used as outcome variables (see Table
Criteria for ARF, definite, probable, possible, potential
To gain a comprehensive overview of ARF episodes a number of sources of data will be examined. These comprise: regional surveillance and notification databases; carer/subject interviews; primary healthcare history reviews; and hospital separation diagnoses.
At time of enrolment an interview of the participants and/or their carers/family will be undertaken. Data collected will comprise: demographics, knowledge of ARF or RHD diagnoses, episodes suggestive of ARF (arthritis/arthralgia), whether the participant is receiving secondary prophylaxis, household crowding and socioeconomic data.
A primary health care and hospital history review will also be undertaken in a representative subset of participants. Data collected during this review will comprise information about potential episodes of ARF, arthritis/arthralgia, chorea and diagnoses of RHD. Clinical data regarding each potential episode of ARF, based on the Australian modified Jones criteria
], will be collected. These data will be used to validate the accuracy of existing register-based ARF notifications.
(b) Progression of valvular abnormalities
Progression of valvular abnormalities will be assessed prospectively using transthoracic echocardiography and standardized operating and reporting procedures already developed and refined for the gECHO study. Briefly the echocardiogram will be undertaken using a Vividi/e portable cardiac ultrasound machine (GE Healthcare) with a standardized machine setup as outlined below.
• Highest frequency transducer that gives adequate penetration,
• Colour gain set by gradually increasing until static background noise barely appears,
• No electrocardiography (ECG) for screening studies,
• ECG for comprehensive studies,
• At least 2 second video acquisition of each view with longer periods for detailed sweeping of potentially abnormal valves
Studies will initially involve a screening echocardiogram which will proceed to a comprehensive study if there is one or more of: mitral regurgitation ≥ 10mm; any aortic regurgitation; any other abnormal mitral or aortic valve findings; or any other pathology present (e.g. abnormal morphology, thickening, multiple regurgitant jets etc.).
Screening echocardiograms will incorporate the views and assessments outlined in Table
. Comprehensive echocardiograms, if required, will incorporate more detailed information based on the abnormalities detected on the screening study and will be undertaken using the views and assessments outlined in Table
. All echocardiograms will be carried out by trained, accredited and practicing echocardiographers.
View and assessments required for RhFFUS screening echocardiogram
Requirement, view and assessments required for RhFFUS comprehensive echocardiogram
Progression of a valve lesion will be defined as one or more of: development of any morphologic or function abnormality in a control subject; development of a new functional or morphologic abnormality in a case; or progression of severity of a functional valve lesion (regurgitation/stenosis) based on standard severity criteria
Progression of valve lesions will be determined by specialist cardiologist readers who will be provided with the initial gECHO screening and subsequent RhFFUS screening echocardiogram for each participant. Studies will be read and assessed individually and then in pairs. The readers will be blinded to the initial gECHO assessment and temporal order of the two echocardiograms. Reporting will use a standardized reporting template.
In order to limit any potential for information bias in this study only the study coordinator at each site will know whether a participant is a case or control. Thus the sonographer carrying out the echocardiogram, the researchers involved in reviewing each participant’s medical history and the cardiologist assessing the echocardiogram will be blinded to the participant’s status as case or control.
All data collected on paper-based forms (participant/carer/family interviews and medical history reviews) will be stored under numerical code in a locked filing cabinet in the RhFFUS study coordinator’s office. Only research personnel will have access to these records.
Reports from the echocardiogram readers will be received in electronic format and will be saved in a password-protected folder on the study coordinator’s computer.
Research staff will transfer the information from both paper forms and electronic echocardiogram reports to an Access database (Microsoft Office Access 2007, Microsoft Corporation, Redmond, Washington, USA) that will be password-protected. De-identified data will be analysed using STATA version 12 (StataCorp, College Station, Tex, USA).
Any information collected will be strictly confidential and no identifying information will be published or disseminated upon completion of the study. Data will be stored for at least 5 years as per Australian National Health and Medical Research Council guidelines
The primary analysis will be based on univariate analysis comparing cases and matched controls. This will include a χ2 analysis comparing the number of children with an episode of ARF (stratified by definite, probable, possible and potential (see Table
)) during the period of follow-up and those who have demonstrated progression of a valve lesion (see above). More detailed analysis will include survival analysis comparing the timing of first episode of ARF to address potential loss of follow-up and Poisson regression for the rate of ARF to address the potential occurrence of more than one episode of ARF occurring in any one individual and a variable period of follow-up. Multivariate techniques (logistic regression and Cox proportional hazard) will be utilized if the matching of cases and controls is not successful and to addresses subsequently identified covariates including the possibility of concomitant prophylactic antibiotics.
RhFFUS has been approved by human ethics research committees in each of the jurisdictions where it will be undertaken. Approval has been granted by the following committees: Darling Downs – West Moreton (Toowoomba and Darling Downs) Health Service District Human Research Ethics Committee (Queensland)(HREC/11/QTDD/10), James Cook University Human Research Ethics Committee (Queensland)(H4136), Central Australian Human Research Ethics Committee (Northern Territory)(HREC-12-35), the Human Research Ethics Committee of Northern Territory department of Health and Menzies School of Health Research (Northern Territory)(HREC-2011-1564), the WA Country Health Service Research Ethics Committee (Western Australia)(2011:31), the Western Australian Aboriginal Health Ethics Committee (Western Australia)(371-10/11), the University of Western Australia Human Research Ethics Committee (Western Australia)(RA/4/1/5313).
The RhFFUS project is funded by the Australian Government through a grant from the National Health and Medical Research Council (NHMRC Project Grant Application 1005951).