Do clinimetric properties of LCI change after correction of signal processing?

Background: The recently described sensor-crosstalk error in the multiple-breath washout (MBW) device (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) could highly influence clinimetric properties and the current interpretation of MBW results. This study reanalyzes MBW data from clinical routine in the corrected software version Spiroware® 3.3.1 and evaluates the effect on outcomes. Methods: We included nitrogen-MBW data from healthy children and children with CF from previously published trials and ongoing cohort studies. We specifically compared LCI analyzed in Spiroware 3.2.1 and 3.3.1 with regards to i) feasibility, ii) repeatability and iii) validity as outcome parameters in children with CF. Results: (i) All previously collected measurements could be reanalyzed and resulted in unchanged feasibility in Spiroware 3.3.1. (ii) Short- and midterm repeatability of LCI was similar in both software versions. (iii) Clinical validity of LCI remained similar in Spiroware 3.3.1, however, resulted in lower values. Discrimination between health and disease was comparable between both software versions. The increase in LCI over time was less pronounced with 0.16 LCI units/year (95% CI 0.08; 0.24) vs. 0.30 LCI units/year (95% CI 0.21; 0.38) in 3.2.1. Response to intervention in children receiving CFTR-modulator therapy resulted in a comparable improvement in LCI in both Spiroware versions. Conclusion: Our study confirms that clinimetric properties of LCI remain unaffected after correction for the cross-sensitivity error in Spiroware software.

The Utility of Pharmacogenetics Testing in Psychiatric Populations

The implementation of pharmacogenetic tests including multiple gene variants has shown promising potential as a decision-making tool for optimizing psychopharmacological treatment regimens and reducing treatment costs. However, the varying clinical validity of gene variants included in pharmacogenetic test batteries, and inconsistencies in their translation into medical recommendations between commercially available pharmacogenetic tests, complicates their rational implementation. Thus, there is a need for well-designed, reproducible studies documenting the clinical significance of the various genetic variants.

P-P38 External validation of post-operative pancreatic fistula prediction scores in pancreatoduodenectomy: a systematic review and meta-analysis

Background Multiple risk scores claim to predict the probability of post-operative pancreatic fistula (POPF) after pancreatoduodenectomy. It is unclear which scores have undergone external validation which score is the most accurate. Objective: To identify risk scores and assess the clinical validity of these scores. Methods Areas under receiving operator characteristic curve (AUROCs) were extracted from studies that performed external validation of POPF risk scores. These were pooled for each risk score, using intercept-only random-effects meta-regression models. Results Systematic review identified 34 risk scores, of which six had been subjected to external validation, and so were included in the meta-analysis, namely the Tokyo (N = 2 validation studies), Birmingham (N = 5), FRS (N = 19), a-FRS (N = 12), m-FRS (N = 3) and ua-FRS (N = 3) scores. The overall predictive accuracies were found to be similar for all six scores, with pooled AUROCs of 0.61, 0.70, 0.71, 0.70, 0.70 and 0.72, respectively. Considerably heterogeneity was observed, with I2 statistics ranging from 52.1-88.6%. Conclusions Most risk scores lack external validation, their predictive accuracies were limited and similar across risk scores. Consensus is needed for which score to use in clinical practice. Due to the limited predictive accuracy, future studies to derive a more accurate risk score are warranted.

Validation of an Acoustic-Based Framework of Speech Motor Control: Assessing Criterion and Construct Validity Using Kinematic and Perceptual Measures

Purpose This study investigated the criterion (analytical and clinical) and construct (divergent) validity of a novel, acoustic-based framework composed of five key components of motor control: Coordination, Consistency, Speed, Precision, and Rate. Method Acoustic and kinematic analyses were performed on audio recordings from 22 subjects with amyotrophic lateral sclerosis during a sequential motion rate task. Perceptual analyses were completed by two licensed speech-language pathologists, who rated each subject's speech on the five framework components and their overall severity. Analytical and clinical validity were assessed by comparing performance on the acoustic features to their kinematic correlates and to clinician ratings of the five components, respectively. Divergent validity of the acoustic-based framework was then assessed by comparing performance on each pair of acoustic features to determine whether the features represent distinct articulatory constructs. Bivariate correlations and partial correlations with severity as a covariate were conducted for each comparison. Results Results revealed moderate-to-strong analytical validity for every acoustic feature, both with and without controlling for severity, and moderate-to-strong clinical validity for all acoustic features except Coordination, without controlling for severity. When severity was included as a covariate, the strong associations for Speed and Precision became weak. Divergent validity was supported by weak-to-moderate pairwise associations between all acoustic features except Speed (second-formant [F2] slope of consonant transition) and Precision (between-consonant variability in F2 slope). Conclusions This study demonstrated that the acoustic-based framework has potential as an objective, valid, and clinically useful tool for profiling articulatory deficits in individuals with speech motor disorders. The findings also suggest that compared to clinician ratings, instrumental measures are more sensitive to subtle differences in articulatory function. With further research, this framework could provide more accurate and reliable characterizations of articulatory impairment, which may eventually increase clinical confidence in the diagnosis and treatment of patients with different articulatory phenotypes.

Development and validity of the Korea psychiatric triage algorithm

Background Psychiatric emergencies require timely intervention because of the risk of harm to individuals and society, including others. The aim of the present study was to test the content validity of a psychiatric triage algorithm developed for use in South Korea. Methods The initial algorithm was developed through systematic literature review. Its validity was then verified by 10 experts. Based on results of expert validity, the algorithm was modified and the final algorithm was developed. Results Its clinical validity was then verified by 37 emergency room nurses who had used triage. Four questions of expert validity results with a CVI of 0.8 or less were revised to reflect expert opinion. The usefulness, adequacy, and convenience of the final modified algorithm was 2.98 ~ 3.53. Conclusion After sufficiently validated by follow-up studies, it is expected that the use of psychiatric classification algorithms in emergency room nurses will not only improve the quality of care, but also can improve patient outcomes and experience.

Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab

To advance the use of circulating tumor DNA (ctDNA) applications, their broad clinical validity must be tested in different treatment settings, including targeted therapies. Utilizing the prespecified longitudinal systematic collection of plasma samples in the phase 1/2a LYM1002 trial (NCT02329847), we tested the clinical validity of ctDNA for baseline mutation profiling, residual tumor load quantification, and acquisition of resistance mutations in patients with lymphoma treated with ibrutinib plus nivolumab. Inclusion criterion for this ancillary biological study was the availability of blood collected at baseline and cycle 3 day 1. Overall, 172 ctDNA samples from 67 patients were analyzed using LyV4.0 ctDNA CAncer Personalized Profiling by deep Sequencing assay. Among baseline variants in ctDNA, only TP53 mutations (detected in 25.4% of patients) were associated with shorter progression-free survival; clones harboring baseline TP53 mutations did not disappear during treatment. Molecular response, defined as a >2-log reduction in ctDNA levels after 2 cycles of therapy (28 days), was achieved by 28.6% of patients with relapsed diffuse large B-cell lymphoma who had ≥1 baseline variant and was associated with best response and improved progression-free survival. Clonal evolution occurred frequently during treatment, and 10.3% new mutations were identified after 2 treatment cycles in nonresponders. PLCG2 was the topmost among genes that acquired new mutations. No patients acquired C481S BTK mutations implicated in resistance to ibrutinib in CLL. Collectively, our results provide the proof of concept that ctDNA is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting.

Clinical validation of brief mental health scales for use in South African occupational healthcare

Orientation: South Africa carries a high burden of mental ill-health. Screening to identify individuals for further referral is emerging as one pathway to promote access to mental health interventions. Existing occupational health surveillance infrastructure may be a useful mechanism for clinical mental health screening.Research purpose: This study explored the clinical validity of a range of brief mental health measures in the context of occupational health surveillance.Motivation for the study: To meaningfully screen for mental health as part of occupational health surveillance, tools are required that are empirically validated, clinically useful, locally available and practical to administer.Research approach/design and method: Workers (n = 1816), recruited through workplace occupational health surveillance programmes, completed the Patient Health Questionnaire-9, Brief Symptom Inventory 18-somatisation subscale, Generalised Anxiety Disorder scale-7, Primary Care Post-Traumatic Stress Disorder Screen, Intense (panic-like) anxiety scale and CAGE scale and partook in a diagnostic interview with a clinical psychologist.Main findings: Basic psychometric characteristics were reported, including confirmatory factor analyses, measurement invariance, internal consistencies and socio-demographic effects. Clinical utility was explored through receiver operating/operator characteristics curve analyses, and calculations of positive and negative predictive values, as well as sensitivity and specificity. These indicators provided evidence of clinical validity in the study context.Practical/managerial implications: The findings support the use of psychological screening as a brief, practicable and easily accessible mode of occupational mental health support.Contribution/value-add: This article presented evidence of structural and criterion validity for these scales and described their clinical application for practical use in occupational mental health surveillance.

Plasma BRAF Mutation Detection for the Diagnostic and Monitoring Trajectory of Patients with LDH-High Stage IV Melanoma

For patients with newly diagnosed metastatic melanoma, rapid BRAF mutation (mBRAF) assessment is vital to promptly initiate systemic therapy. Additionally, blood-based biomarkers are desired to monitor and predict treatment response. Circulating tumor DNA (ctDNA) has shown great promise for minimally invasive mBRAF assessment and treatment monitoring, but validation studies are needed. This prospective study utilized longitudinal plasma samples at regular timepoints (0, 6, 12, 18 weeks) to address the clinical validity of ctDNA measurements in stage IV melanoma patients with elevated serum lactate dehydrogenase (LDH > 250U/L) starting first-line systemic treatment. Using droplet digital PCR, the plasma mBRAF abundance was assessed in 53 patients with a BRAFV600 tissue mutation. Plasma mBRAF was detected in 50/51 patients at baseline (98% sensitivity; median fraction abundance of 19.5%) and 0/17 controls (100% specificity). Patients in whom plasma mBRAF became undetectable during the first 12–18 weeks of treatment had a longer progression-free survival (30.2 vs. 4.0 months; p < 0.001) and cancer-specific survival (not reached vs. 10.2 months; p < 0.001) compared to patients with detectable mBRAF. The ctDNA dynamics outperformed LDH and S100 dynamics. These results confirm the clinical validity of ctDNA measurements as a minimally invasive biomarker for the diagnostic and monitoring trajectory of patients with LDH-high stage IV melanoma.