Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema

OBJECTIVE: There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Our objective was to review the literature on biomarkers and surrogates to develop a hierarchical schema that systematically evaluates and ranks the surrogacy status of biomarkers and surrogates; and to obtain feedback from stakeholders. METHODS: After a systematic search of Medline and Embase on biomarkers, surrogate (outcomes, endpoints, markers, indicators), intermediate endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. RESULTS: The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation level of evidence schema that evaluates biomarkers along 4 domains: Target, Study Design, Statistical Strength, and Penalties. Scores derived from 3 domains the Target that the marker is being substituted for, the Design of the (best) evidence, and the Statistical strength are additive. Penalties are then applied if there is serious counterevidence. A total score (0 to 15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. It was proposed that the term "surrogate" be restricted to markers attaining Levels 1 or 2 only. Most stakeholders agreed that this operationalization of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. CONCLUSION: Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery, development, and approval.     

Scope for improvement in the quality of reporting of systematic reviews. From the Cochrane Musculoskeletal Group

OBJECTIVE: To assess the quality of reporting in Cochrane musculoskeletal systematic reviews (excluding back and injury reviews). METHODS: This study assessed all the Cochrane Musculoskeletal Group's systematic reviews from Issue 4, 2002, of the Cochrane Library Database of Systematic Reviews. Two reviewers independently extracted data and assessed quality. Two assessment tools were used, including an 18 item checklist and flow chart developed by the Quality of Reporting of Meta-analysis (QUOROM) consensus group, and a 10 item scale, the Oxman-Guyatt Overview Quality Assessment Questionnaire (OQAQ). One question on the latter scale (item 10) scores overall quality on a 7 point scale, with high scores indicating superior quality. Data were analyzed using univariate approaches. RESULTS: The 57 systematic reviews assessed were found to have good overall quality, with scores on individual items revealing only minor flaws. Documenting the flow of included and excluded studies and summarizing the results are 2 areas needing improvement in reporting. According to the Oxman-Guyatt scale the overall scientific quality of the Cochrane musculoskeletal reviews was good [mean 5.02 (95% CI 3.71-6.32)]. CONCLUSION: Our study found that the reporting quality of Cochrane musculoskeletal systematic reviews was generally good, although there was room for improvement. For example, it might be feasible to develop specific guidelines for reporting protocols. Certainly more work is needed in reporting search results, documentation of the flow of studies, identification of the type of studies, and summarization of the key findings.     

A comparison of five Illumina,Ion Torrent,and nanopore sequencing technology-based approaches for whole genome sequencing of SARS-CoV-2

Rapid identification of the rise and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern remains critical for monitoring of the efficacy of diagnostics, therapeutics, vaccines, and control strategies. A wide range of SARS-CoV-2 next-generation sequencing (NGS) methods have been developed over the last years, but cross-sequence technology benchmarking studies have been scarce. In the current study, 26 clinical samples were sequenced using five protocols: AmpliSeq SARS-CoV-2 (Illumina), EasySeq RC-PCR SARS-CoV-2 (Illumina/NimaGen), Ion AmpliSeq SARS-CoV-2 (Thermo Fisher), custom primer sets (Oxford Nanopore Technologies (ONT)), and capture probe-based viral metagenomics (Roche/Illumina). Studied parameters included genome coverage, depth of coverage, amplicon distribution, and variant calling. The median SARS-CoV-2 genome coverage of samples with cycle threshold (Ct) values of 30 and lower ranged from 81.6 to 99.8% for, respectively, the ONT protocol and Illumina AmpliSeq protocol. Correlation of coverage with PCR Ct values varied per protocol. Amplicon distribution signatures differed across the methods, with peak differences of up to 4 log₁₀ at disbalanced positions in samples with high viral loads (Ct values ≤ 23). Phylogenetic analyses of consensus sequences showed clustering independent of the workflow used. The proportion of SARS-CoV-2 reads in relation to background sequences, as a (cost-)efficiency metric, was the highest for the EasySeq protocol. The hands-on time was the lowest when using EasySeq and ONT protocols, with the latter additionally having the shortest sequence runtime. In conclusion, the studied protocols differed on a variety of the studied metrics. This study provides data that assist laboratories when selecting protocols for their specific setting.

     

Is group physical therapy superior to individualized therapy in ankylosing spondylitis? A randomized controlled trial

Purpose. To study the effects of adding supervised group physical therapy to unsupervised individualized therapy in ankylosing spondylitis. Methods. One hundred forty-four patients were randomized to exercises at home, or the same plus weekly group physical therapy for 9 months. Endpoints were spinal mobility, fitness[maximum work capacity by ergometry], functioning (Sickness Impact Profile, Health Assessment Questionnaire for the Spondylar-thropathies, and Functional Index), and patient's global assessment of change on a 10-cm visual analogue scale. Results. Thoracolumbar flexion and extension increased by an average of 0.5 cm (9%) after home exercises, and by 0.9 cm (16%) after group therapy. Maximum load in ergometry decreased by 2 W (1%) after home exercises, but increased by 7 W (4%) after group therapy. Global assessment improved by 0.3 (6%)after home exercises, and by 1.7 (34%) after group therapy. These three differenceswere statistically significant. There were no significant differences in chest expansion, cervical rotation, or the self-assessments of functioning. Conclusions. Group physical therapy proved superior to individualized therapy in improving thoracolumbar mobility and fitness, and had an important effect on global health reported by the patients.