The strategic biomarker roadmap for the validation of Alzheimer’s diagnostic biomarkers: methodological update

Abstract

Background The 2017 Alzheimer’s disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1–2), clinical validity (Phases 3–4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research. Methods We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer’s Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers. Results The 2020 update applies to all AD diagnostic biomarkers. In Phases 2–3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures. Discussion This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.

Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

“…As proposed in the updated guidelines of the strategic biomarker roadmap (Boccardi et al [12]) and discussed in the workshop held in Geneva, November 11-12, 2019, the definition of an appropriate standard for diagnostic biomarkers is a critical step in the validation process. Pathology studies are necessary to demonstrate analytical validity.…”

“…The guiding principle of the present framework was based on the phases delineated for biomarker development in oncology by Pepe et al (2001), with specific adaptations to reflect the screening and diagnosis process for AD (Boccardi et al [12]). The present review assessed the maturity of the secondgeneration tau PET tracers with regard to each of the following phases and is detailed below: Phase 1 Phase 1 studies are preclinical exploratory studies aimed at identifying the rational of the biomarker based on pathology findings.…”

“…Previous studies with this shared objective assessed this 5-phase framework with other known biomarkers: cerebrospinal fluid (CSF) assessment of amyloid and tau pathology [7], medial temporal atrophy [8], FDG-PET [9] and 123 I-ioflupane brain single photon emission tomography, 123 I-MIBG cardiac scintigraphy [10], and episodic memory impairment [11]. The strategic biomarker roadmap methodology has then been revised (Boccardi et al [12]) to incorporate the most recent theoretical advancements as well as to accommodate biomarkers of tauopathy.…”

Molecular imaging and fluid biomarkers of Alzheimer’s disease neuropathology: an opportunity for integrated diagnostics

“…The main steps of the validation process of AD biomarkers have been formalized in a Strategic Biomarker Roadmap, resulting from the collaborative work of a group of experts in the diagnosis of cognitive disturbances and biomarkers [1]. The roadmap, updated based on recent theoretical advancement [2], outlines the methodology required to produce and assess evidence of analytical validity, clinical validity, and clinical utility for each biomarker. This framework provides therefore a systematic tool to identify the gaps in knowledge that should be filled with priority to allow evidence-based clinical and policy decisions.…”

“…There are only a few diagnostic studies measuring this parameter [10][11][12], one in this issue comparing the incremental diagnostic value of amyloid PET and tau PET [13]. The limited evidence on the comparison and combination of biomarkers presumably contributes to explain the variable policies for coverage across countries and the lack of widely accepted detailed diagnostic algorithms [1,2]. Moreover, diagnostic algorithms need to be specific for different contexts of use.…”