APP1135277_Rice_Grant Proposal

GRANT PROPOSAL – 2016 Centres of Research Application ID: 1135277
Excellence funding commencing 2017 CIA Surname: Rice
implemented within routine pathology. The data obtained will inform and facilitate the development
and clinical uptake early pregnancy screening and triage to treatment.
Program 3 formalises an In Vitro Diagnostic medical device development core that is NATA
accredited for ISO17025, complies with ISO13485. During the life of the CRE, application will
also be made for accreditation for ISO15198 (Medical Testing). As such, this Program will be the
only such accredited facility in Australia. It will provide a unique clinical research, development
and training environment for scientific and clinical practitioners and an enabling capacity for
leadership development.
PROGRAM 4: Triage to High-risk Management
First trimester screening algorithms for PE, IUGR and GDM have already been developed. There
are a number of processes that need to be completed before these tools for individualised precision
medicine can be robustly applied to population based screening. First, continued algorithmic
development with inclusion of other biomarkers (Program 2) will improve screening efficacy
(sensitivity, specificity and predictive values) and facilitate development of algorithms for preterm
birth. Second, these algorithms need validation in separate populations to demonstrate applicability
and consistency in performance. Third, the impact of preventative interventions applied based on
the findings of first trimester screening (and therefore the value of prediction and prevention) needs
to be demonstrated. These processes can potentially be completed simultaneously in multicentre
randomised controlled trials that enrol patients prior to screening, randomising them to an
intervention on the basis of the initial predictive test result.
Research Questions:
• Can the performance of current first trimester screening algorithms be reproduced in
multiple centres with different population groups?
• Can screening efficacy be improved by inclusion of other exosome or genome derived
biomarkers?
• Are preventative interventions (aspirin for PE and IUGR; metformin for late PE; diet and
lifestyle advice / metformin / probiotics for GDM; progesterone / cerclage for preterm
labour) effective in reducing disease prevalence for women defined as being at high risk of
an adverse pregnancy outcome?
Study Rationale: There is a clear need to collect more evidence-based data to define the clinical
utility of first trimester risk assignment algorithms and to examine the impact of preventative
therapeutic interventions. We have already developed multivariate algorithms to classify risk for
subsequent development of PE, IUGR and GDM. The tests can variously be criticised for poor
sensitivity (IUGR, late onset PE) and/or positive predictive value (early onset PE) and may be
improved by including exosomal biomarkers or genomic markers. Novel algorithms, based on
inclusion of these factors, can be compared to our current standards by comparing test performance
through calculation of screening efficacy (sensitivity and specificity and positive and negative
predictive values) and receiver operator characteristic curve analysis. Screening and identification
of risk is only of value if preventative strategies are available that improve health outcomes. A
number of interventions that prevent PE/ IUGR, GDM and spontaneous preterm birth have been
proposed. Application is typically impacted by poor prediction of a high-risk group. The combined
prediction and prevention strategy therefore needs assessing through a multicentre randomised
controlled study.
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