Methods for the evaluation of biomarkers in patients with kidney and liver diseases: multicentre research programme including ELUCIDATE RCT
Selby, PJ; Banks, RE; Gregory, W; et al.Hewison, J; Rosenberg, W; Altman, DG; Deeks, JJ; McCabe, C; Parkes, J; Sturgeon, C; Thompson, D; Twiddy, M; Bestall, J; Bedlington, J; Hale, T; Dinnes, J; Jones, M; Lewington, A; Messenger, MP; Napp, V; Sitch, A; Tanwar, S; Vasudev, NS; Baxter, P; Bell, S; Cairns, DA; Calder, N; Corrigan, N; Del Galdo, F; Heudtlass, P; Hornigold, N; Hulme, C; Hutchinson, M; Lippiatt, C; Livingstone, T; Longo, R; Potton, M; Roberts, S; Sim, S; Trainor, S; Welberry Smith, M; Neuberger, J; Thorburn, D; Richardson, P; Christie, J; Sheerin, N; McKane, W; Gibbs, P; Edwards, A; Soomro, N; Adeyoju, A; Stewart, GD; Hrouda, D
Date: 31 July 2018
Journal
Programme Grants for Applied Research
Publisher
NIHR Journals Library
Publisher DOI
Abstract
Background: Protein biomarkers with associations with the activity and outcomes of diseases are being
identified by modern proteomic technologies. They may be simple, accessible, cheap and safe tests that
can inform diagnosis, prognosis, treatment selection, monitoring of disease activity and therapy and may
substitute for complex, ...
Background: Protein biomarkers with associations with the activity and outcomes of diseases are being
identified by modern proteomic technologies. They may be simple, accessible, cheap and safe tests that
can inform diagnosis, prognosis, treatment selection, monitoring of disease activity and therapy and may
substitute for complex, invasive and expensive tests. However, their potential is not yet being realised.
Design and methods: The study consisted of three workstreams to create a framework for research:
workstream 1, methodology – to define current practice and explore methodology innovations for biomarkers
for monitoring disease; workstream 2, clinical translation – to create a framework of research practice,
high-quality samples and related clinical data to evaluate the validity and clinical utility of protein biomarkers;
and workstream 3, the ELF to Uncover Cirrhosis as an Indication for Diagnosis and Action for Treatable Event
(ELUCIDATE) randomised controlled trial (RCT) – an exemplar RCT of an established test, the ADVIA Centaur®
Enhanced Liver Fibrosis (ELF) test (Siemens Healthcare Diagnostics Ltd, Camberley, UK) [consisting of a panel
of three markers – (1) serum hyaluronic acid, (2) amino-terminal propeptide of type III procollagen and
(3) tissue inhibitor of metalloproteinase 1], for liver cirrhosis to determine its impact on diagnostic timing
and the management of cirrhosis and the process of care and improving outcomes.
Results: The methodology workstream evaluated the quality of recommendations for using prostate-specific
antigen to monitor patients, systematically reviewed RCTs of monitoring strategies and reviewed the
monitoring biomarker literature and how monitoring can have an impact on outcomes. Simulation studies
were conducted to evaluate monitoring and improve the merits of health care. The monitoring biomarker
literature is modest and robust conclusions are infrequent. We recommend improvements in research
practice. Patients strongly endorsed the need for robust and conclusive research in this area. The clinical
translation workstream focused on analytical and clinical validity. Cohorts were established for renal cell
carcinoma (RCC) and renal transplantation (RT), with samples and patient data from multiple centres, as a
rapid-access resource to evaluate the validity of biomarkers. Candidate biomarkers for RCC and RT were
identified from the literature and their quality was evaluated and selected biomarkers were prioritised. The
duration of follow-up was a limitation but biomarkers were identified that may be taken forward for clinical
utility. In the third workstream, the ELUCIDATE trial registered 1303 patients and randomised 878 patients
out of a target of 1000. The trial started late and recruited slowly initially but ultimately recruited with good
statistical power to answer the key questions. ELF monitoring altered the patient process of care and may
show benefits from the early introduction of interventions with further follow-up. The ELUCIDATE trial was
an ‘exemplar’ trial that has demonstrated the challenges of evaluating biomarker strategies in ‘end-to-end’
RCTs and will inform future study designs.
Conclusions: The limitations in the programme were principally that, during the collection and curation
of the cohorts of patients with RCC and RT, the pace of discovery of new biomarkers in commercial and
non-commercial research was slower than anticipated and so conclusive evaluations using the cohorts are
few; however, access to the cohorts will be sustained for future new biomarkers. The ELUCIDATE trial was
slow to start and recruit to, with a late surge of recruitment, and so final conclusions about the impact of
the ELF test on long-term outcomes await further follow-up. The findings from the three workstreams
were used to synthesise a strategy and framework for future biomarker evaluations incorporating
innovations in study design, health economics and health informatics.
Institute of Health Research
Collections of Former Colleges
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