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. 2021 Jul;48(7):2157-2168.
doi: 10.1007/s00259-020-05187-x. Epub 2021 Feb 17.

Outcomes of clinical utility in amyloid-PET studies: state of art and future perspectives

Matteo Cotta Ramusino  1   2 , Giulia Perini  1   2 , Daniele Altomare  3   4 , Paola Barbarino  5 , Wendy Weidner  5 , Gabriella Salvini Porro  6 , Frederik Barkhof  7   8 , Gil D Rabinovici  9 , Wiesje M van der Flier  10 , Giovanni B Frisoni  3   4 , Valentina Garibotto  11   12 , Stefan Teipel  13   14 , Marina Boccardi  15
Affiliations

Outcomes of clinical utility in amyloid-PET studies: state of art and future perspectives

Matteo Cotta Ramusino et al. Eur J Nucl Med Mol Imaging. 2021 Jul.

Abstract

Purpose: To review how outcomes of clinical utility are operationalized in current amyloid-PET validation studies, to prepare for formal assessment of clinical utility of amyloid-PET-based diagnosis.

Methods: Systematic review of amyloid-PET research studies published up to April 2020 that included outcomes of clinical utility. We extracted and analyzed (a) outcome categories, (b) their definition, and (c) their methods of assessment.

Results: Thirty-two studies were eligible. (a) Outcome categories were clinician-centered (found in 25/32 studies, 78%), patient-/caregiver-centered (in 9/32 studies, 28%), and health economics-centered (5/32, 16%). (b) Definition: Outcomes were mainly defined by clinical researchers; only the ABIDE study expressly included stakeholders in group discussions. Clinician-centered outcomes mainly consisted of incremental diagnostic value (25/32, 78%) and change in patient management (17/32, 53%); patient-/caregiver-centered outcomes considered distress after amyloid-pet-based diagnosis disclosure (8/32, 25%), including quantified burden of procedure for patients' outcomes (n = 8) (1/8, 12.5%), impact of disclosure of results (6/8, 75%), and psychological implications of biomarker-based diagnosis (75%); and health economics outcomes focused on costs to achieve a high-confidence etiological diagnosis (5/32, 16%) and impact on quality of life (1/32, 3%). (c) Assessment: all outcome categories were operationalized inconsistently across studies, employing 26 different tools without formal rationale for selection.

Conclusion: Current studies validating amyloid-PET already assessed outcomes for clinical utility, although non-clinician-based outcomes were inconsistent. A wider participation of stakeholders may help produce a more thorough and systematic definition and assessment of outcomes of clinical utility and help collect evidence informing decisions on reimbursement of amyloid-PET.

Keywords: Alzheimer’s disease; Amyloid-PET; Clinical utility; Diagnostic biomarkers; Outcome; Systematic review.

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Conflict of interest statement

V. Garibotto received financial support for research through her institution from Siemens Healthineers, GE Healthcare, Life Molecular Imaging, Cerveau Technologies, Roche, Merck. G.D. Rabinovici receives research support from the National Institutes of Health, Alzheimer’s Association, American College of Radiology, Rainwater Charitable Foundation, Gift from Edward and Pearl Fein, Avid Radiopharamaceuticals, Eli Lilly, Life Molecular Imaging, GE Healthcare. He has served as a consultant for Axon Neurosciences, Eisai, GE Healthcare, Merck, Genentech. He serves on a data safety monitoring board for Johnson & Johnson. He is an Associate Editor for JAMA Neurology.

F. Barkhof is a member of steering committee and safety monitoring boards for Merck, Biogen and Bayer. He is a consultant for Novartis, Roche, IXICO, GeNeuro, and Combinostics; his institutions received research support from EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EPAD and AMYPAD consortia), Horizon (EuroPOND), UK MS Society, IMDI-NOW (PICTURE), NIHR UCLH Biomedical Research Centre, and ECTRIMS-MAGNIMS. He is section Editor for Neuroradiology. The other authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
The strategic biomarker roadmap validation phases targeted by the studies included in this review [5, 6]. This figure is a derivative from “The Strategic Biomarker Roadmap for the validation of Alzheimer’s diagnostic biomarkers: methodological update” by M. Boccardi et al [6], used under a Creative Commons Attribution 4.0 International License CC-BY (http://creativecommons.org/licenses/by/4.0/legalcode). The outcomes of interest for this review are those relative to phase 4 and phase 5 that is not yet investigated in amyloid-PET studies. Phase 4 studies require to replicate evidence of clinical validity in real world samples, and allow to collect preliminary information concerning costs and impact on disease burden, thus preparing the methods required for the systematic evaluation of clinical utility in phase 5 studies. Therefore, phase 4 studies include preliminary measures of clinical utility answering secondary aims 2–3 (continuous red circle), and measures of clinical utility sometimes used as surrogate measures of clinical validity to answer the primary aim (red dotted circle): Phase 4/primary aim target: To determine the operating characteristics of the biomarker-based diagnostic test in MCI patients in the memory clinics population (replicating the phase 3 accuracy studies in a real-world context). Phase 4/secondary aim 2: To assess the practical feasibility of implementing the biomarker-based diagnostic procedure and compliance of test-positive subjects with workup recommendations. (In this aim we also included emotional and social implications related to the positive result disclosure.) Phase 4/secondary aim 3: To make preliminary assessments of the effects of biomarker-based diagnosis on costs and burden associated with AD
Fig. 2
Fig. 2
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of selected papers
See this image and copyright information in PMC

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