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Introduction The Modena bleeding score is a categorical rating scale that allows the assessment of the surgical field in relation to bleeding during endoscopic surgery. It has recently been presented and validated in the field of endoscopic ear surgery by the present authors. The Modena bleeding score provides five grades for rating the surgical field during endoscopic procedures (from grade 1 − no bleeding to grade 5 − bleeding that prevents every surgical procedure except those dedicated to bleeding control). Objective The aim of this study was to validate the Modena bleeding score in the setting of endoscopic sinus surgery. Methods Fifteen three-minute videos of endoscopic sinus surgery procedures (each containing three bleeding situations) were evaluated by 15 specialists, using the Modena bleeding score. Intra and inter-rater reliability were assessed, and the clinical validity of the Modena bleeding score was calculated using a referent standard. Results The data analysis showed an intra-rater reliability ranging from 0.6336 to 0.861. The inter-rater reliability ranged from 0.676 to 0.844. The clinical validity was α = 0.70; confidence limits: 0.64 − 0.75, corresponding to substantial agreement. Conclusion The Modena bleeding score is an effective method to score bleeding during endoscopic sinus surgery. Its application in future research could facilitate the performance and efficacy assessment of surgical techniques, materials or devices aimed to bleeding control during endoscopic sinus surgery.

Purpose In 2017, the Geneva Alzheimer’s disease (AD) Biomarker Roadmap initiative adapted the framework of the systematic validation of oncological diagnostic biomarkers to AD biomarkers, with the aim to accelerate their development and implementation in clinical practice. With this work, we assess the maturity of [18F]flortaucipir PET and define its research priorities. Methods The level of maturity of [18F]flortaucipir was assessed based on the AD Biomarker Roadmap. The framework assesses analytical validity (phases 1–2), clinical validity (phases 3–4), and clinical utility (phase 5). Results The main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. [18F]Flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties and excellent discriminative accuracy for AD. The majority of secondary aims of phase 2 were fully achieved. Multiple studies showed high correlations between ante-mortem [18F]flortaucipir PET and post-mortem tau (as assessed by histopathology), and also the effects of covariates on tracer binding are well studied. The aims of phase 3 (early detection ability) were only partially or preliminarily achieved, and the aims of phases 4 and 5 were not achieved. Conclusion Current literature provides partial evidence for clinical utility of [18F]flortaucipir PET. The aims for phases 1 and 2 were mostly achieved. Phase 3 studies are currently ongoing. Future studies including representative MCI populations and a focus on healthcare outcomes are required to establish full maturity of phases 4 and 5.

Time in glucose ranges is increasingly relevant for research and clinical practice. Whereas the clinical validity of these metrics has been demonstrated with regard to long-term complications, their associations with patient-reported outcomes such as well-being, diabetes distress, and fear of hypoglycemia remain an open research question. This article reviews existing evidence on links between times in glycemic ranges and patient-reported outcomes. It also describes a novel research approach of using ecological momentary assessment to analyze on a more granular level in real time possible associations of these parameters of glycemic control and patient-reported outcomes. Such an approach could further our understanding of how glucose and patient-reported outcomes may be interconnected.

Technological innovations reach deeply into our daily lives and an emerging trend supports the use of commercial smart wearable devices to manage health. In the era of remote, decentralized and increasingly personalized patient care, catalysed by the COVID-19 pandemic, the cardiovascular community must familiarize itself with the wearable technologies on the market and their wide range of clinical applications. In this Review, we highlight the basic engineering principles of common wearable sensors and where they can be error-prone. We also examine the role of these devices in the remote screening and diagnosis of common cardiovascular diseases, such as arrhythmias, and in the management of patients with established cardiovascular conditions, for example, heart failure. To date, challenges such as device accuracy, clinical validity, a lack of standardized regulatory policies and concerns for patient privacy are still hindering the widespread adoption of smart wearable technologies in clinical practice. We present several recommendations to navigate these challenges and propose a simple and practical ‘ABCD’ guide for clinicians, personalized to their specific practice needs, to accelerate the integration of these devices into the clinical workflow for optimal patient care., In this Review, Elshazly and colleagues summarize the basic engineering principles of common wearable sensors and discuss their broad applications in cardiovascular disease prevention, diagnosis and management., Key points Smart wearables generate a plethora of data through various sensors and software algorithms and understanding their basic engineering principles and limitations can be helpful for clinicians and scientists.Evidence supports the use of wearable devices in cardiovascular risk assessment and cardiovascular disease prevention, diagnosis and management, but large, well-designed trials are needed to establish their advantages.Several challenges still hinder the widespread adoption of wearables in clinical practice, including a concern for device accuracy, patient privacy and cost, and how to separate actionable data from noise.Overcoming these challenges requires that various stakeholders come together to develop comprehensive evaluation frameworks, pragmatic regulatory policies, clinical trials and medical education curricula.A practical ‘ABCD’ guide for clinicians can facilitate the integration of these devices in routine clinical practice.

Circulating graft-derived cell-free DNA (dd-cfDNA) is a new marker of cardiac allograft damage that is used for noninvasive rejection diagnostics. We performed dd-cfDNA (%) in heart transplant recipients during the first posttransplant year.In 87 patients, serial dd-cfDNA determination at predefined time-points was performed in 770 single samples. dd-cfDNA fraction (%) was measured using an established universal droplet digital polymerase chain reaction method, providing same-day turn-around. Rejection was diagnosed according to clinical parameters and biopsies.Median dd-cfDNA (%) was high (5.36%) immediately after reperfusion and decreased to a median (interquartile range) of 0.10% (0.05%-0.24%) in clinically stable patients by postoperative day 10. Compared to dd-cfDNA (%) samples in clinically stable patients, values were higher (P0.001) in biopsy-proven rejection ISHLT 1R (0.42% [0.15%-0.53%]) and 2R rejection (0.84% [0.39%-0.97%]). Moreover, dd-cfDNA (%) was already significantly increased 9-30 days before biopsy-proven rejection (0.36% [0.20%-0.61%]). An as yet unknown finding was a slightly, but significantly (P0.0001) higher dd-cfDNA (%) value in samples of stable patients with pericardial effusions (PEs) (n = 94; 0.18% [0.07%-0.30%]) compared to samples of non-PE patients (n = 132; 0.07% [0.04%-0.17%]). Using a cutoff of 0.35%, sensitivity and specificity of dd-cfDNA for cardiac rejection were 0.76 and 0.83 (area under the curve [AUC] ROC-curve: 0.81 [95% confidence interval, 0.73-0.89]). Omitting PE samples from the control group yielded an AUC of 0.86 [95% confidence interval, 0.76-0.95]. Samples drawn12 hours after endomyocardial biopsy showed high (0.40% [0.15%-1.21%]) dd-cfDNA values, also in ISHLT0R (0.36% [0.10%-0.60%]).dd-cfDNA plasma values were significantly associated with cardiac rejection. However, PE or improper sampling (eg, shortly after biopsy) should be considered as confounders for rejection diagnoses using dd-cfDNA.

Artificial intelligence (AI) will likely affect various fields of medicine. This article aims to explain the fundamental principles of clinical validation, device approval, and insurance coverage decisions of AI algorithms for medical diagnosis and prediction. Discrimination accuracy of AI algorithms is often evaluated with the Dice similarity coefficient, sensitivity, specificity, and traditional or free-response receiver operating characteristic curves. Calibration accuracy should also be assessed, especially for algorithms that provide probabilities to users. As current AI algorithms have limited generalizability to real-world practice, clinical validation of AI should put it to proper external testing and assisting roles. External testing could adopt diagnostic case-control or diagnostic cohort designs. A diagnostic case-control study evaluates the technical validity/accuracy of AI while the latter tests the clinical validity/accuracy of AI in samples representing target patients in real-world clinical scenarios. Ultimate clinical validation of AI requires evaluations of its impact on patient outcomes, referred to as clinical utility, and for which randomized clinical trials are ideal. Device approval of AI is typically granted with proof of technical validity/accuracy and thus does not intend to directly indicate if AI is beneficial for patient care or if it improves patient outcomes. Neither can it categorically address the issue of limited generalizability of AI. After achieving device approval, it is up to medical professionals to determine if the approved AI algorithms are beneficial for real-world patient care. Insurance coverage decisions generally require a demonstration of clinical utility that the use of AI has improved patient outcomes.

The prognostic role of circulating tumor cells (CTCs) has been clearly demonstrated in many types of cancer. However, their roles in diagnostic and treatment strategies remain to be defined. In this review, we present an overview of the current clinical validity of CTCs in nonmetastatic and metastatic cancer, and the main studies or concepts investigating the clinical utility of CTCs. In particular, we focus on breast, lung, colorectal, and prostate cancer. Two major topics concerning the clinical utility of CTC are discussed: treatment based on CTC count or CTC variations, and treatment based on the molecular characteristics of CTCs. Although some of these studies are inconclusive, many are still ongoing, and their results could help to define the role of CTCs in the management of cancers. A summary of published or ongoing phase II‐III trials is also presented., This review article discusses the clinical utility of circulating tumor cells (CTCs) in various settings of screening and treatment of non‐metastatic and metastatic tumors. Two major aspects are considered, namely i) treatment based on CTC count or CTC variations, and ii) treatment based on the molecular characteristics of CTCs. A summary of published or ongoing phase II‐III trials with CTCs is also presented.

Aim: Evaluate the accuracy of a 23-gene expression signature in differentiating benign nevi from melanoma by comparing test results with clinical outcomes. Materials & methods: Seven dermatopathologists blinded to gene expression test results and clinical outcomes examined 181 lesions to identify diagnostically uncertain cases. Participants independently recorded diagnoses and responses to questions quantifying diagnostic certainty. Test accuracy was determined through comparison with clinical outcomes (sensitivity and percent negative agreement). Results: Overall, 125 cases fulfilled criteria for diagnostic uncertainty (69.1%; 95% CI: 61.8–75.7%). Test sensitivity and percent negative agreement in these cases were 90.4% (95% CI: 79.0–96.8%) and 95.5% (95% CI: 87.3–99.1%), respectively. Conclusion: The 23-gene expression signature has high diagnostic accuracy in diagnostically uncertain cases when evaluated against clinical outcomes.

OBJECTIVES The aim of the study was to investigate the role of combined multichannel intraluminal impedance and pH (MII-pH) testing in clinical management of children with gastroesophageal reflux disease (GERD) by exploring the impact of treatment changes made based on MII-pH testing results on symptoms and quality of life outcomes. METHODS All patients (

Molecular testing for genomic variants is recommended in advanced non-small cell lung cancer (NSCLC). Standard tissue biopsy is sometimes infeasible, procedurally risky, or insufficient in tumor tissue quantity. We present the analytical validation and concordance study of EGFR variants using a new 17-gene liquid biopsy assay (NCT02762877). Of 144 patients enrolled with newly diagnosed or progressive stage IV nonsquamous NSCLC, 140 (97%) had liquid assay results, and 117 (81%) had both EGFR blood and tissue results. Alterations were detected in 58% of liquid samples. Overall tissue-liquid concordance for EGFR alterations was 94.0% (95% CI 88.1%, 97.6%) with positive percent agreement of 76.7% (57.7%, 90.1%) and negative percent agreement of 100% (95.8%, 100%). Concordance for ALK structural variants was 95.7% (90.1%, 98.6%). This assay detected alterations in other therapeutically relevant genes at a rate similar to tissue analysis. These results demonstrate the analytical and clinical validity of this 17-gene assay.

Valentin Petre Matei,1 Alexandra Ioana Mihăilescu,1,2 Iuliana Raluca Gheorghe,3 Ruxandra Grigoraş,4 Andrei Crasan,5 Alina Roșca,1,6 Ovidiu Popa-Velea2 1Clinical Hospital of Psychiatry “Alexandru Obregia”, Bucharest, Romania; 2Department of Medical Psychology, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; 3Department of Marketing and Medical Technology, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; 4Voila Psychiatric Hospital, Câmpina, Romania; 5The City Hospital of Curtea De Argeş, Curtea De Argeș, Romania; 6Department of Psychiatry, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, RomaniaCorrespondence: Iuliana Raluca Gheorghe Email raluca.gheorghe@umfcd.roPurpose: This study examined the validity of subjective clinical prognosis (SCP), a commonly used clinical tool, in first episode psychosis patients included in the European First Episode Schizophrenia Trial (EUFEST) study.Patients and Methods: The study comprised 455 patients from the EUFEST trial (mean age 25.92, SD=5.45; 188 (41.31%) women, 267 (58.69%) men). SCP was classified into three mutually exclusive groups: “good prognosis” (GP) (n=265), “average prognosis” (AP) (n=131), and “poor prognosis” (PP) (n=59). The validity of the SCP was assessed by investigating the differences between the SCP groups and completer or responder status of the patients, during 1 year of the trial.Results: The proportion of completers was significantly higher in the GP group (64.4%) compared to the AP group (25.6%) (OR=1.62, 95% CI=1.062– 2.476, p< 0.031) and the PP group (10%) (OR=2.17, 95% CI=1.226– 3.853, p< 0.009) throughout the whole duration of the trial. In what concerns responsiveness, a significantly higher number of responders were registered in the GP group compared to the AP and the PP groups in the first three months of treatment, but this outcome did not persist afterwards.Conclusion: In terms of its predictive value at first episode schizophrenic patients, SCP seems to be reliable for treatment completion, but has a limited utility in what concerns responsiveness to treatment. This finding suggests the necessity of creating a prediction model potentially including, besides SCP, other measurement-based variables.Keywords: anti-psychotics, first episode psychosis, prognosis, schizophrenia

Objective: To assess the outcome of psychotherapeutic treatments, psychotherapy researchers often compare pre- and post-treatment scores on self-report outcome measures. In this paper, the common assumption is challenged that pre-to-post decreasing and increasing outcome scores are indicative of successful and failed therapies, respectively.Method: The outcome of 29 psychotherapeutic treatments was evaluated by means of quantitative analysis of pre- and post-treatment scores on commonly used outcome measures (such as the Symptom Checklist-90-R, the Inventory of Interpersonal Problems, and the General Health Questionnaire-12), as well as through consensual qualitative research.Results: Overall, a moderate to low convergence between qualitative and quantitative evaluations of outcome was observed. Detailed analyses of six cases are presented in which pre-to-post comparisons of outcome measures proved misleading.Conclusions: It is concluded that psychotherapy outcome research might benefit from assessment strategies that are sensitive to the singularities of individual treatments and to the complexity of the phenomenon of therapeutic outcome. Furthermore, classical psychometric evaluations of the validity of outcome measures might be supplemented with less-systematic evaluations that take any contingent source of information on outcome into account.

Whether individual results of genetic research studies ought to be disclosed to study participants has been debated in recent decades. Previously, the prevailing expert view discouraged the return of individual research results to participants because of the potential lack of analytic validity, questionable clinical validity and medical actionability, and questions about whether it is the role of research to provide participants with their data. With additional knowledge of participant perspectives and shifting views about the benefits of research and respect for participants, current expert consensus is moving toward support of returning such results. Significant ethical controversies remain, and there are many practical questions left to address, including appropriate procedures for returning results and the potential burden to clinicians when patients seek guidance about the clinical implications of research results. In this review, we describe current views regarding the return of genetic research results, including controversies and practical challenges, and consider the application of these issues to research on apolipoprotein L1 (APOL1), a gene recently associated with health disparities in kidney disease. Although this case is unique, it illustrates the complexities involved in returning results and highlights remaining questions.

Purpose Despite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include. Methods To inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT. Results We identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria. Conclusion Opportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.

Pharmacogenomic testing in clinical psychiatry has grown at an accelerated pace in the last few years and is poised to grow even further. Despite robust evidence lacking regarding efficacy in clinical use, there continues to be growing interest to use it to make treatment decisions. We intend this article to be a primer for a clinician wishing to understand the biological bases, evidence for benefits, and pitfalls in clinical decision-making. Using clinical vignettes, we elucidate these headings in addition to providing a perspective on current relevance, what can be communicated to patients, and future research directions. Overall, the evidence for pharmacogenomic testing in psychiatry demonstrates strong analytical validity, modest clinical validity, and virtually no evidence to support clinical use. There is definitely a need for more double-blinded randomized controlled trials to assess the use of pharmacogenomic testing in clinical decision-making and care, and until this is done, they could perhaps have an adjunct role in clinical decision-making but minimal use in leading the initial treatment plan.

The decision to administer adjuvant chemotherapy in treatment of early invasive breast cancer (EBC) is often complex, particularly for hormone receptor-positive (HR+) diseases, and current guidelines often classify these patients in an intermediate-risk group. Several biomarkers are currently available in this indication, in order to obtain additional and more accurate prognostic information compared to classic clinicopathological characteristics and guide the indication of adjuvant chemotherapy, optimizing the efficacy/toxicity ratio. We conducted a systematic review to evaluate the clinical validity and clinical utility of five biomarkers (uPA/PAI-1, OncotypeDX®, MammaPrint®, PAM50, and EndoPredict®) in HR+/HER2- EBC, whatever the nodal status. A total of 89 studies met the inclusion criteria. Even though data currently available confirm the clinical validity of these biomarkers, there is a lack of data regarding clinical utility for most of them. Prospective studies in well-defined populations are needed to integrate these biomarkers in a decision strategy.

Magnetic resonance imaging (MRI) has an established role in the assessment of degenerative musculoskeletal conditions. However, conventional supine MRI findings often correlate poorly with clinical findings. Some patients experience accentuated back pain in the weight-bearing position. Therefore, supine MRI may underestimate the severity of degenerative spine findings. To try and improve the clinical validity of spine imaging, axial loading devices have been used with conventional supine MR imaging to simulate loading of the upright spine. More recently, upright weight-bearing MRI systems (0.25–0.6 T) were introduced, allowing images to be obtained in the standing or seated weight-bearing position and even during upright flexion or extension, rotation, or bending. Some scanners even enable capturing of real-time spinal movement. This review addresses the technical aspects and potential challenges of weight-bearing MRI, both in clinical practice and research.

Background Hereditary breast and ovarian cancer syndrome (HBOC) is caused by pathogenic variants in BRCA and other cancer-related genes. We analyzed variants in BRCA gene and other cancer-related genes in HBOC patients to evaluate the clinical validity of next-generation sequencing (NGS) multi-gene panel testing. Methods The BRCA1/2 NGS testing was conducted for 262 HBOC patients. Multiplex ligation-dependent probe amplification and direct Sanger sequencing were performed for confirmation. Multi-gene panel testing was conducted for 120 patients who did not possess BRCA1/2 pathogenic variants but met the National Comprehensive Cancer Network criteria. Results Pathogenic variants in BRCA1/2 were detected in 30 HBOC patients (11.5%). Additionally, four out of the 120 patients possessed pathogenic variants by multi-gene panel testing (3.3%): MSH2 (c.256G>T, p.Glu86*), PMS2 (c.1687C>T, p.Arg563*), CHEK2 (c.546C>A, p.Tyr182*), and PALB2 (c.3351-1G>C). All the four patients had a family history of cancer. Conclusions Multi-gene panel testing could be a significant screening tool for HBOC patients, especially for those with a family history of cancer.

Newborn screening is an incredibly useful tool for the early identification of many metabolic disorders, including fatty acid oxidation (FAO) disorders. In many cases, molecular tests are necessary to reach a final diagnosis, highlighting the need for a thorough evaluation of genes implicated in FAO disorders. Using the ClinGen (Clinical Genome Resource) clinical validity framework, thirty genes were analyzed for the strength of evidence supporting their association with FAO disorders. Evidence was gathered from the literature by biocurators and presented to disease experts for review in order to assign a clinical validity classification of Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Reported Evidence. Of the gene-disease relationships evaluated, 22/30 were classified as Definitive, three as Moderate, one as Limited, three as No Reported Evidence and one as Disputed. Gene-disease relationships with a Limited, Disputed, and No Reported Evidence were found on two, six, and up to four panels out of 30 FAO disorder-specific panels, respectively, in the National Institute of Health Genetic Testing Registry, while over 70% of the genes on panels are definitively associated with an FAO disorder. These results highlight the need to systematically assess the clinical relevance of genes implicated in fatty acid oxidation disorders in order to improve the interpretation of genetic testing results and diagnosis of patients with these disorders.

Background/purpose: The electronic clinical decision support system (CDSS) is mainly used to assist health care providers in their decision-making process. CDSS includes the dose range checking (DRC) tool. This study aims to evaluate the clinical validity of the DRC tool and compare it to the institutional Formulary and Drug Therapy Guide powered by Lexi-Comp. Methods: This retrospective study analyzed DRC alerts in the inpatient setting. Alerts were assessed for their clinical validity when compared to recommendations of the institution’s formulary. Relevant data regarding patient demographics and characteristics were collected. A sample size of 3000 DRC alerts was needed to give a margin of error of 1% (using normal approximation to binomial distribution gives 30.26/3000 = 1%). Results: In our cohort, 1659 (55%) of the DRC alerts were generated for adult patients. A total of 1557 (52%) of all medication-related DRC alerts recommended renal dose adjustments, while 708 (24%) needed hepatic dose adjustments. Majority of alerts, 2844 (95%), were clinically invalid. A total of 2892 (96%) alerts were overridden by prescribers. In 997 (33%) cases, there was an overdose relative to the recommended dose, and in 1572 (52%) there was underdosing. Residents were more likely to accept the DRC alerts compared with other health provider categories ( P < .001). Conclusion: Using DRC as a clinical decision support tool with minimal integration yielded serious clinically invalid recommendations. This could increase medication-prescribing errors and lead to alert fatigue in electronic health care systems.

Noninvasive prenatal testing (NIPT) utilizes cell-free fetal DNA (cffDNA) present in maternal peripheral blood to detect chromosomal abnormalities. The detection of 21-trisomy, 18-trisomy, and 13-trisomy in the fetus has become a common screening method during pregnancy and has been widely applied in routine clinical testing because of its analytical and clinical validity. Currently, noninvasive prenatal testing involving copy number variations (CNVs) and other frequent single-gene disorders is being widely studied, and it plays an important and indispensable role in prenatal detection. The multiple approaches that have been reported and validated by various laboratories have different merits and limitations. Their clinical validity, utility, and application vary with different diseases. This review summarizes the principles, methods, advantages, and limitations of noninvasive prenatal testing for the detection of aneuploidy, CNVs and single-gene disorders. Before implementation of NIPT into clinical practice, a list of criteria that the application must meet is crucial. Essential parameters such as clinical sensitivity, clinical specificity, positive predictive value (PPV) and negative predictive value (NPV) are required to properly evaluate the clinical validity and utility of NIPT. We then discuss and analyze these clinical parameters and clinical application guidelines, providing physicians and scientists with feasible strategies and the latest research information.

Purpose: Gene-disease associations implicated in hereditary colorectal cancer and polyposis susceptibility were evaluated using the ClinGen Clinical Validity framework. Methods: Forty-two gene-disease pairs were assessed for strength of evidence supporting an association with hereditary colorectal cancer and/or polyposis. Genetic and experimental evidence supporting each gene-disease relationship was curated independently by two trained biocurators. Evidence was reviewed with experts and assigned a final clinical validity classification. Results: Of all gene-disease pairs evaluated, 14/42 (33.3%) were Definitive, 1/42 (2.4%) were Strong, 6/42 (14.3%) were Moderate, 18/42 (42.9%) were Limited, and 3/42 (7.1%) were either No Reported Evidence, Disputed, or Refuted. Of panels in the NIH Genetic Testing Registry, 4/26 (~15.4%) contain genes with Limited clinical evidence. Conclusion: Clinicians and laboratory diagnosticians should note that 40% have only Moderate, Limited, Disputed, or Refuted evidence. Continuing to expand the structured assessment of the clinical relevance of genes listed on hereditary cancer testing panels will help clinicians and diagnostic laboratories focus the communication of genetic testing results on clinically significant genes.

Objectives The main objective was to examine the effect of central maturation on the auditory temporal resolution in a group of school-age children using Gaps-In-Noise test. Methods The study involved 180 children (6–16 years) with normal hearing, average intelligence and language skills, and adequate scholastic achievement. Subjects were divided into four age subgroups. Investigations involved basic audiological evaluation, screening test battery for central auditory processing, and finally Gaps-In-Noise test. Results Comparison of the four age subgroups revealed non-significant age effect on the Gaps-In-Noise test. The approximate gap detection threshold of children was comparable to that of adults. Equivalent data were obtained as a function of the ear, gender, list, and retest. Conclusion Central auditory maturation of the temporal resolution and hence the Gaps-In-Noise test has been established by age 5 years. Consequently, assessment of Gaps-In-Noise test in school-age children provided adult-like normative data. The stability of outcomes across different factors highlights the clinical validity of Gaps-In-Noise test in the assessment of temporal resolution deficit and follow-up after remediation.

PURPOSE: Several genes on hereditary breast and ovarian cancer susceptibility test panels have not been systematically examined for strength of association with disease.We employed the Clinical Genome Resource (ClinGen) clinical validity framework to assess the strength of evidence between selected genes and breast or ovarian cancer. METHODS: Thirty-one genes offered on cancer panel testing were selected for evaluation. The strength of gene-disease relationship was systematically evaluated and a clinical validity classification of either Definitive, Strong, Moderate, Limited, Refuted, Disputed or No clinical evidence was assigned. RESULTS: Definitive clinical validity classifications were made for 10/31 and 10/32 gene-disease pairs for breast and ovarian cancer respectively. Two genes had a Moderate classification whereas, 6/31 and 6/32 genes had Limited classifications for breast and ovarian cancer respectively. Contradictory evidence resulted in Disputed or Refuted assertions for 9/31 genes for breast and 4/32 genes for ovarian cancer. No Reported Evidence of disease association was asserted for 5/31 genes for breast and 11/32 for ovarian cancer. CONCLUSION: Evaluation of gene-disease association using the ClinGen clinical validity framework revealed a wide range of classifications. This information should aid laboratories in tailoring appropriate gene panels and assist health care providers interpret results from panel testing.

Expanded carrier screening (ECS) panels that use next‐generation sequencing aim to identify pathogenic variants in coding and clinically relevant non‐coding regions of hundreds of genes, each associated with a serious recessive condition. ECS has established analytical validity and clinical utility, meaning that variants are accurately identified and pathogenic variants tend to alter patients' clinical management, respectively. However, the clinical validity of ECS, that is, correct discernment of whether an identified variant is indeed pathogenic, has only been shown for single conditions, not for panels. Here, we evaluate the clinical validity of a >170‐condition ECS panel by assessing concordance between >12 000 variant interpretations classified with guideline‐based criteria to their corresponding per‐variant combined classifications in ClinVar. We observe 99% concordance at the level of unique variants. A more clinically relevant frequency‐weighted analysis reveals that fewer than 1 in 500 patients are expected to receive a report with a variant that has a discordant classification. Importantly, gene‐level concordance is not diminished for rare ECS conditions, suggesting that large panels do not balloon the panel‐wide false‐positive rate. Finally, because ECS is intended to serve all reproductive‐age couples, we show that classification of novel variants is feasible and scales predictably for a large population.

Name of the disease (synonyms) CUGC for posterior polymorphous corneal dystrophy (PPCD). OMIM# of the disease 122000; 609141; 618031. Name of the analysed genes or DNA/chromosome segments OVOL2 (PPCD1); ZEB1 (PPCD3); GRHL2 (PPCD4). OMIM# of the gene(s) 616441; 189909; 608576. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for variants in the OVOL2, ZEB1 and GRHL2 gene(s) in a diagnostic setting, predictive and parental settings and for risk assesment in relatives.

OBJECTIVE To validate the Comprehensive Complication Index (CCI) via an assessment of its relation to postoperative costs. BACKGROUND The CCI summarizes all the postoperative complications graded by the Clavien-Dindo classification (CDC) on a numerical scale. Its relation to hospital costs has not been validated to date. METHODS Prospective observational cohort study, including all patients undergoing surgery at a general surgery service during the 1-year study period. All complications graded with the CDC and CCI and related to the initial admission, or until discharge if the patient was readmitted within 90 days of surgery, were included. The surgeries were classified according to their Operative Severity Score (OSS) and in 4 groups of homogeneous surgeries. All postoperative costs were recorded. RESULTS In all, 1850 patients were included, of whom 513 presented complications (27.7%). The CDC and the CCI were moderately to strongly correlated with overall postoperative costs (OPCs) in all OSS groups (rs = 0.444-0.810 vs 0.445-0.820; P < 0.001), homogeneous surgeries (rs = 0.364-0.802 vs 0.364-0.813; P < 0.001), prolongation of postoperative stay (rs = 0.802 vs 0.830; P < 0.001), and initial operating room costs (rs = 0.448 vs 0.451; P < 0.001). This correlation was higher in emergency surgery. With higher CDC grades, the OPC tended to increase an upward trend. In the multivariate analysis, CDC, CCI, age, and duration of surgery were all associated with OPC (P < 0.001). CONCLUSIONS In our environment, the CCI presented associations with OPC. This demonstration of its economic validity enhances its clinical validity.

To investigate the clinical validity of the mathematical measured VVOR test results to detect horizontal semicircular canal hypofunction.Prospective, nonrandomized, observational study.Tertiary referral center, hospital.Consecutive patients on first time visit to otoneurology unit.Diagnostic.Values of statistical indicators of clinical validity for VVOR test to detect horizontal canal hypofunction were used considering vHIT horizontal aVOR gain values as gold standard.Area under curve of ROC curve for quantified VVOR testing was 0.92. Head movement frequency on VVOR test and contralateral VVOR gain were identified as significant influence factors of (unilateral) VVOR gain (p 0.0001) on statistical linear model.According to the obtained results, the quantified VVOR test has excellent clinical validity for detecting angular horizontal VOR hypofunction.

With the approval of new therapies targeting the PI3K pathway, the detection of PIK3CA mutations has become a key factor in treatment management for HR+/HER2− metastatic breast cancer (MBC). We developed multiplex digital PCR (dPCR) assays to detect and quantify PIK3CA mutations. A first screening assay allows the detection of 21 mutations, with a drop-off system targeting the 542–546 hotspot mutations combined with the simultaneous detection of N345K, C420R, H1047L and H1047R mutations. In the case of a positive result, a sequential strategy based on other assays that we have developped allows for precise mutation identification. Clinical validity was determined by analyzing plasma circulating free DNA (cfDNA) from 213 HR+/HER2− MBC samples, as well as DNA extracted from 97 available matched tumors from 89 patients. Our assays have shown reliable specificity, accuracy and reproducibility, with limits of blank of three and four droplets for the screening assay. Sixty-eight patients (32%) had at least one PIK3CA mutation detectable in their plasma, and we obtained 83.1% agreement between the cfDNA analysis and the corresponding tumors. The high sensitivity and robustness of these new dPCR assays make them well-suited for rapid and cost-effective detection of PIK3CA mutations in the plasma of MBC patients.

Purpose In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer’s disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers—encompassing the 42 amino-acid isoform of amyloid-β (Aβ42), phosphorylated-tau (P-tau), and Total-tau (T-tau)—with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology. Methods A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop. Results By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aβ42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability. Conclusions Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.

Background Endobronchial ultrasound-guided transbronchial needle aspiration is recommended for lymph node (LN) staging in lung cancer. Although 22-gauge needles are widely used, they may make some stations difficult to puncture owing to an acute angle. A thinner 25-gauge needle was introduced in Japan at the end of 2016 and offered structural advantages such as improved flexibility and penetrability. We aimed to validate the clinical utility of the 25-gauge needle in LN staging. Methods Patients who underwent endobronchial ultrasound-guided transbronchial needle aspiration for LN staging of lung cancer using the 25-gauge needle at our institution between November 2016 and March 2019 were included. Patient characteristics, staging procedures, pathology findings, and genetic testing success rates were assessed. Results Data of 130 patients were included in the analysis. The sampling rate was 87.6% (589/672 lesions). In addition to stations #4R, #7, and #11, which are generally easy to puncture, multiple stations (40.1%) were sampled. The diagnostic accuracy of combined computed tomography and fluorodeoxyglucose positron emission tomography was 82.3% and that of additional endobronchial ultrasound-guided transbronchial needle aspiration was 96.9%. The overall sensitivity, specificity, and positive and negative predictive values validated using resected specimens were 97.1% (34/35), 100% (41/41), 100% (34/34), and 97.6% (41/42), respectively. The success rate of genetic testing was 100% (34/34). Conclusions The new 25-gauge needle enabled us to approach a wide range of LNs with a desirable sampling rate and diagnostic accuracy in LN staging using endobronchial ultrasound-guided transbronchial needle aspiration, while providing enough tissue for genetic testing.

© 2020 The Authors Early Intervention in Psychiatry Published by John Wiley & Sons Australia, LtdAim: Clinical staging of schizophrenia entails a new method that identifies clusters of symptoms and variation in level of remission, with the goal to create a framework for early intervention. Additionally, duration of untreated psychosis (DUP) may influence symptom severity in the first episode of psychosis (FEP) and could necessitate refining of the staging model. However, consistent evidence concerning variation in symptom severity and DUP between stages is missing. Therefore, we evaluated the clinical validity of the staging model by investigating differences in symptom severity across stages in schizophrenia spectrum disorders. Second, we assessed if a prolonged DUP is associated with higher symptom severity in FEP. Methods: We performed a cross-sectional study of 291 acutely admitted patients with a schizophrenia spectrum disorder. Patients were assigned to clinical stages following the definition of McGorry. Symptom severity was evaluated with the new DSM-5 Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS). In FEP, we determined the DUP. Results: Significantly higher severity scores of CRDPSS items hallucinations (H = 14.34, df = 4, P-value =.006), negative symptoms (H = 19.678, df = 4, P-value =.001) and impaired cognition (H = 26.294, df = 4, P-value =

Patient’s understanding on forthcoming dental surgeries is required by patient-centered care and helps reduce anxiety. Due to the complexity of dental surgeries and the patient-dentist expertise gap, conventional techniques of patient education are usually not effective for explaining surgical steps. In this paper, we present OralViewer—the first interactive application that enables dentist’s demonstration of dental surgeries in 3D to promote patients’ understanding. OralViewer takes a single 2D panoramic dental X-ray to reconstruct patient-specific 3D teeth structures, which are then assembled with registered gum and jaw bone models for complete oral cavity modeling. During the demonstration, OralViewer enables dentists to show surgery steps with virtual dental instruments that can animate effects on a 3D model in real-time. A technical evaluation shows that our deep learning model achieves a mean Intersection over Union (IoU) of 0.771 for 3D teeth reconstruction. A patient study with 12 participants shows OralViewer can improve patients’ understanding of surgeries. A preliminary expert study with 3 board-certified dentists further verifies the clinical validity of our system.

The compulsive habit model proposed by Everitt and Robbins has accumulated important empirical evidence. One of their proposals is the existence of an axis, on which each a person with a particular addiction can be located depending on the evolutionary moment of his/her addictive process. The objective of the present study is to contribute in addressing the identification of such axis, as few studies related to it have been published to date. To do so, the use/abuse of Information and Communication Technologies (ICT) was quantified on an initial sample of 807 subjects. Questionnaires were also delivered to measure impulsivity, compulsivity and symptoms of prefrontal dysfunction. Evidence of the existence of the proposed axis was obtained by means of Machine Learning techniques, thus allowing the classification of each subject along the continuum. The present study provides preliminary evidence of the existence of the Impulsivity-Compulsivity axis, as well as an IT tool so that each patient that starts getting treatment for an addiction can be statistically classified as “impulsive” or “compulsive.” This would allow the matching of each person with the most appropriate treatment depending on his/her moment in the addiction/abuse process, thus facilitating the individualized design of each therapeutic process and a possible improvement of the results of the treatment.

Simple Summary Currently, the most commonly used method to monitor response to treatment in metastatic breast cancer patients is by radiological imaging. However, these imaging techniques are relatively insensitive and give little to no insight into biological tumor characteristics that might be relevant for the choice of treatment. Circulating tumor DNA (ctDNA), released by tumor cells into the blood of cancer patients, can be used to overcome these shortcomings. Besides the fact that specific alterations are known to predict response to treatment and development of resistance, the total amount of ctDNA is believed to reflect the proliferation rate of the tumor, suggesting ctDNA levels can be used as a general tool to evaluate treatment response. Different methods are available to measure ctDNA primarily based on detection of cancer-specific somatic mutations, DNA methylation, and copy number variations. In this review we have critically analyzed recently published studies using blood-derived ctDNA of metastatic breast cancer patients on multiple time points to monitor disease response in respect to analytical validity and clinical utility. Abstract Monitoring treatment response in metastatic breast cancer currently consists mainly of radiological and clinical assessments. These methods have high inter-observer variation, suboptimal sensitivity to determine response to treatment and give little insight into the biological characteristics of the tumor. Assessing circulating tumor DNA (ctDNA) over time could be employed to address these limitations. Several ways to quantify and characterize ctDNA exist, based on somatic mutations, copy number variations, methylation, and global circulating cell-free DNA (cfDNA) fragment sizes and concentrations. These methods are being explored and technically validated, but to date none of these methods are applied clinically. We systematically reviewed the literature on the use of quantitative ctDNA measurements over time to monitor response to systemic therapy in patients with metastatic breast cancer. Cochrane, Embase, PubMed and Google Scholar databases were searched to find studies focusing on the use of cfDNA to longitudinally monitor treatment response in advanced breast cancer patients until October 2020. This resulted in a total of 33 studies which met the inclusion criteria. These studies were heterogeneous in (pre-)processing procedures, applied techniques and design. An association between ctDNA and treatment response was found in most of the included studies, independent of the applied assay. To implement ctDNA-based response monitoring into daily clinical practice for metastatic breast cancer patients, sample (pre-) processing procedures need to be standardized and large prospectively collected sample cohorts with well annotated clinical follow-up are required to establish its clinical validity.

Measurement of serum neurofilament light chain concentration (sNfL) promises to become a convenient, cost effective and meaningful adjunct for multiple sclerosis (MS) prognostication as well as monitoring disease activity in response to treatment. Despite the remarkable progress and an ever-increasing literature supporting the potential role of sNfL in MS over the last 5 years, a number of hurdles remain before this test can be integrated into routine clinical practice. In this review we highlight these hurdles, broadly classified by concerns relating to clinical validity and analytical validity. After setting out an aspirational roadmap as to how many of these issues can be overcome, we conclude by sharing our vision of the current and future role of sNfL assays in MS clinical practice.

Predictive biomarkers play an important role in our efforts to individualize pharmacotherapy, and within recent years, a number of different types of assays have been introduced. These biomarkers may potentially support the selection and dosage of specific drugs in order to maximize efficacy and minimize adverse reactions in the individual patient. However, in many instances, the scientific and clinical evidence is insufficient to support the prescribing decision. When predictive biomarkers are used to guide pharmacotherapy, it is important to secure that decisions are based on solid clinical evidence. Here, the regulatory authorities, especially the FDA, have been at the forefront in relation to regulate this type of biomarker assay in order to secure patient safety. The approval process for companion diagnostics is an example of this effort, where the scientific validity of the biomarker and assay is in focus. With the approaching implementation of the new IVD Regulation, greater attention will also be paid to analytical and clinical validity of biomarker assays in the EU. For any type of predictive biomarker assay, including pharmacogenetic and tumour profiling tests, the clinical evidence needs to be in place before they are used routinely in the clinic.

Clinical oncology is experiencing rapid growth in data that are collected to enhance cancer care. With recent advances in the field of artificial intelligence (AI), there is now a computational basis to integrate and synthesize this growing body of multi-dimensional data, deduce patterns, and predict outcomes to improve shared patient and clinician decision making. While there is high potential, significant challenges remain. In this perspective, we propose a pathway of clinical cancer care touchpoints for narrow-task AI applications and review a selection of applications. We describe the challenges faced in the clinical translation of AI and propose solutions. We also suggest paths forward in weaving AI into individualized patient care, with an emphasis on clinical validity, utility, and usability. By illuminating these issues in the context of current AI applications for clinical oncology, we hope to help advance meaningful investigations that will ultimately translate to real-world clinical use.

The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.

Objective We determined the reliability of The Kiddie-Schedule for Affective Disorders and Schizophrenia for School- Age Children–Present and Lifetime (K-SADS-PL) for screening and diagnosing ADHD in children. Method K-SADS-PL was administered to 2,074 children in the community. Psychometric properties, factorial structure, and clinical validity of K-SADS-PL in screening or diagnosis of ADHD were examined. Results Internal consistency was excellent for items in the screening interview (Macdonald’s Omega [ω] = 0.89; 95% confidence interval [CI] [0.87, 0.94]) and diagnostic supplement (ω = 0.95; 95% CI [0.92, 0.99]). The standardized coefficients for items in the screening interview were acceptable (0.59-0.85), while fit indices for single factorial structure reached acceptable levels. Screening items were associated with high sensitivity (97.8%; 95% CI [97.2, 98.5%]) and specificity (94.0%; 95% CI [93.0, 95.0%]) for diagnosis of ADHD in the supplement. The test-retest and interinformant reliability as measured by intraclass correlation coefficient was good for most of the items. Conclusion This large study shows that K-SADS-PL can be reliably used to screen and diagnose ADHD in children in Kenya.

We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes.

Purpose To develop a preliminary clinical validation the NANDA-I nursing diagnosis "Grieving" in cases of perinatal loss. Methods Descriptive cross-sectional study using the Fehring model. Findings The overall clinical validity index for the diagnosis was 0.15. Only four defining characteristics and five manifestations identified in the literature were validated. Conclusions The variability of manifestations identified in the study participants is considered to be detrimental to the overall clinical validity index. Implications for nursing practice The clinical validity of the diagnosis could not be substantiated by the preliminary results of this study and, therefore, additional research is necessary to determine the ability of the diagnosis to adapt to perinatal loss situations in real contexts. Some manifestations have been proposed to NANDA-I for inclusion as defining characteristics in the nursing diagnosis of grieving. Objetivo Validar clinicamente de forma preliminar el diagnostico enfermero NANDA-I duelo en caso de perdida perinatal. METODOS: Estudio descriptivo transversal usando el modelo de Fehring. Resultados El indice de validez clinica global del diagnostico fue de 0.15. Se validaron unicamente cuatro caracteristicas definitorias y cinco manifestaciones identificadas en la literatura. Conclusiones Se considera que la variabilidad de las manifestaciones presentadas por los participantes actuo en detrimento del indice de validacion clinica global. IMPLICACIONES PARA LA PRACTICA ENFERMERA: La validez clinica del diagnostico no pudo ser corroborada por los resultados preliminares de este estudio y, por tanto, se necesita investigacion adicional para terminar la capacidad de este diagnostico para adaptarse a las situaciones de perdidas perinatales en contexto reales. Se han propuesto a NANDA-I algunas manifestaciones para que sean incluidas como Caracteristicas Definitorias del diagnostico enfermero Duelo.

Chest X-ray (CXR) is an essential first-line tool in COVID-19 pneumonia diagnosis and management. Our study aimed at assessing 1) CXR manifestations, frequency, and distribution; 2) the feasibility and repeatability of a CXR severity score; and 3) the correlation between the CXR severity score and clinical and laboratory parameters. We reviewed baseline CXRs and clinical data of consecutive patients who presented to our emergency department and resulted positive at SARS-CoV-2 reverse transcriptase-PCR oropharyngeal swab test from March 1, 2020 to April 6, 2020. Lung abnormalities and their distribution were analyzed. A score of CXR severity was assigned by two radiologists, independently, according to the extent of lung involvement, with a maximum score of 8 for CXR. Correlations between the CXR score and the clinical data were assessed. One hundred fifty-five patients were included; 143/155 (92%) were positive at baseline CXR. Ground-glass opacity was the most common finding (141/143, 99%). Involvement was mainly bilateral (96/143, 67%), with peripheral distribution (79/143, 55%). The mean CXR severity score was 3.3 (±2); interobserver agreement was excellent, with a Cohen's K correlation coefficient of 0.901. The CXR score showed a significant positive correlation with C-reactive protein, lactate dehydrogenase, and fever duration, and a negative correlation with oxygen saturation. Chest X-ray findings are in line with those reported by computed tomography studies. The use of a visual CXR score, easy to assess and highly reproducible, can reflect the clinical severity and help the patients' management.

Background There is a need for valid and reliable biomarkers in hidradenitis suppurativa (HS) for diagnosis and disease activity monitoring. Imaging-based biomarkers have the potential to fulfil this unmet need but no evaluation of analytical or clinical validity has yet been undertaken. Objectives To evaluate the analytical and clinical validity of sonographic epidermal thickness, Doppler ultrasound and dermal tunnel diameter in patients with HS. Methods Twenty-two participants with HS were recruited and underwent a total of 65 matched ultrasound and skin biopsies of lesional, perilesional and unaffected tissue. Ultrasound measurements were performed in triplicate with mean values used. Skin biopsies underwent immunohistochemistry as per previously published methods. Analytical validity was assessed in individual ultrasound-biopsy pairs (n = 65) by comparisons of sonographic variables with histological correlates. Clinical validity was assessed in individual patients (n = 22) by comparing measures of overall disease activity with sonographic outcomes. Results Epidermal thickness, dermal tunnel diameter and power Doppler intensity were assessed. Sonographic epidermal thickness and dermal tunnel diameter have high analytical validity with corresponding histological measurements. Power Doppler intensity demonstrated high correlation with dermal CD3+ and CD11c+ cell counts but not neutrophil elastase-positive cells. Power Doppler ultrasound has significant correlation with pain scores, abscess and nodule count, International HS Severity Scoring System score and number of draining tunnels. Conclusions Sonographic epidermal thickness and dermal tunnel diameter have acceptable levels of analytical validity in the assessment of HS lesions. Power Doppler intensity demonstrates acceptable clinical and analytical validity, suggesting it is a valid imaging-based biomarker in HS.

The Non-Union Scoring System (NUSS) aims to classify non-unions according to their severity and relate them to four treatment categories. The main purpose of this study was to evaluate the reliability of the NUSS. In addition we assessed its clinical validity. Forty-four Patients with a tibia non-union between 2005 and 2015 were included in this study. Data from all included patients were scored independently by three observers according to the NUSS criteria. The interobserver agreement was evaluated using the intraclass correlation coefficient (ICC). The interobserver agreement of the Weber–Cech system was assessed using Fleiss’ kappa. Finally, the clinical validity of the NUSS was analysed by comparing outcomes of the actual treatment groups to the proposed treatment groups following from the NUSS scores. Forty-four patients were included. The comparison of NUSS scores between observers showed substantial agreement [ICC; 0.78 (0.67–0.86)]. The comparison of the Weber–Cech classification between observers showed only fair agreement [Fleiss κ; 0.30 (0.17–0.42)]. The χ2 test for the treatment groups according to the NUSS and the treatments at index procedure showed an independent relation (χ2 = 5.794, 6 degrees of freedom, p: 0.447). In contrast, the proposed treatment strategy corresponds well to the definitive treatment (χ2 = 29.963, 9 degrees of freedom, p

Background A Target Product Profile (TPP) outlines the necessary characteristics of an innovative product to address an unmet clinical need. TPPs could be used to better guide manufacturers in the development of ‘fit for purpose’ tests, thus increasing the likelihood that novel tests will progress from bench to bedside. However, there is currently no guidance on how to produce a TPP specifically for medical tests. Methods A systematic review was conducted to summarise the methods currently used to develop TPPs for medical tests, the sources used to inform these recommendations and the test characteristics for which targets are made. Database and website searches were conducted in November 2018. TPPs written in English for any medical test were included. Based on an existing framework, test characteristics were clustered into commonly recognised themes. Results Forty-four TPPs were identified, all of which focused on diagnostic tests for infectious diseases. Three core decision-making phases for developing TPPs were identified: scoping, drafting and consensus-building. Consultations with experts and the literature mostly informed the scoping and drafting of TPPs. All TPPs provided information on unmet clinical need and desirable analytical performance, and the majority specified clinical validity characteristics. Few TPPs described specifications for clinical utility, and none included cost-effectiveness. Conclusions We have identified a commonly used framework that could be beneficial for anyone interested in drafting a TPP for a medical test. Currently, key outcomes such as utility and cost-effectiveness are largely overlooked within TPPs though and we foresee this as an area for further improvement.

Name of the disease (synonyms) Simpson-Golabi-Behmel syndrome (SGBS). OMIM# OF THE DISEASE: 312870. Name of the analysed genes or dna/chromosome segments GPC3. OMIM# OF THE GENE(S): 300037. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the GPC3 gene(s) in ⊠ diagnostic, ☐ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.

Background Rates of sleep disturbances vary widely across pediatric cancer studies, partly due to differences in measurement tools. Patient-reported outcomes measurement information system (PROMIS) offers a rigorously developed, well-validated pair of pediatric sleep health instruments needed to advance sleep research and clinical practice in pediatric cancer. The current study evaluated the clinical validity of PROMIS pediatric sleep scales (sleep disturbances [SD] and sleep-related impairment [SRI]) among children in active cancer treatment. Procedure Caregiver-patient dyads were enrolled during cancer treatment in 2-12 months after diagnosis: 45 children (ages 8-17 years) and 102 caregivers of children (ages 5-17 years) completed PROMIS SD and SRI 8-item short form self-report or caregiver-proxy scales, and caregivers reported the prior week's cancer treatments and blood counts. Results Both scales demonstrated strong internal consistency reliability across reporters. SD and SRI were higher than the PROMIS general population calibration sample for caregivers and patients. Oncology caregivers reported lower SD and SRI than sleep clinic caregivers, but oncology patients were similar to sleep clinic patients. Convergent validity was evidenced through moderate correlations between scales by reporter and both scales being significantly higher in patients taking medications for sleep. There were no significant differences in SD or SRI by diagnostic group, receiving radiation, or having low blood counts. Conclusion The PROMIS SD and SRI short forms are promising measures for pediatric oncology, demonstrating strong internal consistency reliability and multiple indications of clinical validity. Although groups did not differ based on treatment variables, results suggest the need for universal screening for sleep problems during pediatric cancer treatment.

There exists ongoing debate regarding the clinical validity of single symptoms of and diagnostic criteria for gaming disorder. In particular, the potential symptom of gaming disorder that addresses coping with and escaping from negative feelings has received much attention and remains a focus of intensive discussion. We argue that it is important to consider differences or distinguish between, on the one hand, symptoms of and criteria for a disorder due to addictive behaviors, such as gaming disorder, versus, on the other hand, motivations, mechanisms, and psychological processes that may be involved in promoting addictive behaviors and that may explain symptom severity and course of the addictive disorder including potential treatment responses.

Purpose Paucity of reliable long-term data on the prognostic implications of the 2004 WHO bladder cancer classification system necessitates utilisation of both this and the 1973 grading systems. This study evaluated, in noninvasive (pTa) bladder tumours, the prognostic value of the 2004 system independently and in combination with the 1973 system while establishing concordance between tertiary centre uropathologists. Methods We used a cohort of non-muscle invasive bladder cancer (NMIBC) patients diagnosed between 1991 and 93 where tumour features were gathered prospectively with detailed cystoscopic follow-up data recorded over 15 years. Initial grading was by one senior expert uropathologist (UP1) using the 1973 WHO classification alone. Subsequently, two other expert uropathologists (UP2 and UP3), blinded to the previous grading, re-evaluated the pathology slides and graded the tumours using both the 1973 and 2004 systems. Association between grade and recurrence/progression was analysed and the Cohen Kappa test assessed concordance between pathologists. Results Of 370 new NMIBC, 229 were staged noninvasive (pTa). Recurrence rates were 46.2% and 50.0% for LGPUC (low-grade papillary urothelial carcinoma) and HGPUC (high-grade papillary urothelial carcinoma), respectively, while progression was seen in 3.9% and 10.0% of LGPUC and HGPUC, respectively. Concordance between uropathologists UP2 and UP3 for the 2004 and 1973 systems was good (Kappa = 0.69) and fair (Kappa = 0.25), respectively. Conclusions With good inter-observer concordance, the 2004 WHO classification system of noninvasive bladder tumours appears to accurately predict recurrence and progression risks. The combination of both grading systems to low-grade tumours allows further refinement of the natural history.