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BACKGROUND: With the availability of disease-modifying therapies for Alzheimers disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.

Awareness of the importance of assessing social cognition skills under conditions showing atypical social behaviours has increased over the years. However, the evaluation of the psychometric properties of the measures and the availability of normative values for the clinical context are still limited. This study aims to revise, provide normative values, and evaluate the clinical validity of the Italian version of three social cognition measures: Advanced Theory of Mind (A-ToM) task, the Emotion Attribution Task (EAT), and the Social Situation Task (SST). Measures were administered to 580 adolescents and adult healthy controls (age range 14–50). We performed differential item functioning and Rasch analysis to revise each task, so normative data of the revised measures were calculated. Moreover, the revised measures were administered to 38 individuals with autism spectrum disorder (ASD) and 35 individuals with schizophrenia spectrum disorders (SSD): ASD and SSD were matched by age, gender, and IQ with a control sample to evaluate clinical validity. ROC analysis showed that the SST is the best measure differentiating between healthy and clinical groups, compared to the A-ToM (AUCASD = 0.70; AUCSSD = 0.65) and EAT (AUCASD = 0.67; AUCSSD = 0.50), which showed poorer performance. For SSD diagnosis, two SST subscales (Violation and Gravity score) indicated the best accuracy (AUCs of 0.88 and 0.84, respectively); for the ASD diagnosis, we propose a combined score between the SST subscale and A-ToM (AUC = 0.86). The results suggest that the proposed measures can be used to support the diagnostic process and clinical practice. [ABSTRACT FROM AUTHOR]

Genome-based testing in oncology is a rapidly expanding area of health care that is the basis of the emerging area of precision medicine. The efficient and considered adoption of novel genomic medicine testing is hampered in Canada by the fragmented nature of health care oversight as well as by lack of clear and transparent processes to support rapid evaluation, assessment, and implementation of genomic tests. This article provides an overview of some key barriers and proposes approaches to addressing these challenges as a potential pathway to developing a national approach to genomic medicine in oncology. [ABSTRACT FROM AUTHOR]

Genome-based testing in oncology is a rapidly expanding area of health care that is the basis of the emerging area of precision medicine. The efficient and considered adoption of novel genomic medicine testing is hampered in Canada by the fragmented nature of health care oversight as well as by lack of clear and transparent processes to support rapid evaluation, assessment, and implementation of genomic tests. This article provides an overview of some key barriers and proposes approaches to addressing these challenges as a potential pathway to developing a national approach to genomic medicine in oncology.

Single-gene disorders (SGDs), also known as monogenic disorders, are caused by pathogenic variants at individual loci. Prenatal cell-free DNA screening for SGDs has been investigated for decades. Detecting paternal and de novo variants may be somewhat straightforward, whereas detecting maternally inherited variants poses a significant challenge. Although commercially available in both high-risk and low-risk patients, many limitations exist. The use of SGDs is not supported by professional medical societies. [ABSTRACT FROM AUTHOR]

HepB LiveTest is a machine learning decision support system developed for the early detection of hepatitis B virus (HBV). However, there is a lack of evidence on its generalisability. In this study, we aimed to externally assess the clinical validity and portability of HepB LiveTest in predicting HBV infection among independent patient cohorts from Nigeria and Australia. The performance of HepB LiveTest was evaluated by constructing receiver operating characteristic curves and estimating the area under the curve. Delong's method was used to estimate the 95% confidence interval (CI) of the area under the receiver-operating characteristic curve (AUROC). Compared to the Australian cohort, patients in the derivation cohort of HepB LiveTest and the hospital-based Nigerian cohort were younger (mean age, 45.5 years vs. 38.8 years vs. 40.8 years, respectively; p < 0.001) and had a higher incidence of HBV infection (1.9% vs. 69.4% vs. 57.3%). In the hospital-based Nigerian cohort, HepB LiveTest performed optimally with an AUROC of 0.94 (95% CI, 0.91–0.97). The model provided tailored predictions that ensured most cases of HBV infection did not go undetected. However, its discriminatory measure dropped to 0.60 (95% CI, 0.56–0.64) in the Australian cohort. These findings indicate that HepB LiveTest exhibits adequate cross-site transportability and clinical validity in the hospital-based Nigerian patient cohort but shows limited performance in the Australian cohort. Whilst HepB LiveTest holds promise for reducing HBV prevalence in underserved populations, caution is warranted when implementing the model in older populations, particularly in regions with low incidence of HBV infection. [ABSTRACT FROM AUTHOR]

Abstract Background Psychotic experiences are reported in the general population. The Questionnaire for Psychotic Experiences (QPE) was created to test the phenomenological features of these experiences and compare them with those reported in patients with psychiatric and other medical conditions. The aim of this study was to test the psychometric properties of the Arabic version of the QPE. Methods We recruited 50 patients with psychotic disorders from the Hamad Medical Hospital in Doha, Qatar. Patients underwent assessment over three sessions with trained interviewees using the Arabic versions of QPE, Positive and Negative Syndrome Scale (PANSS), Beck Depression Inventory (BDI), and the Global Assessment of Functioning Scale (GAF). Patients were also reassessed using the QPE and GAF after 14-days from the initial assessment in order to test for the stability of the scale. In this respect, this is the first study that assesses the test–retest reliability of the QPE. The psychometric properties including convergent validity, stability, and internal consistency met the benchmarked criteria. Results Results confirmed that the Arabic version of QPE accurately measured the experiences of patients that were also reported using the PANSS, an internationally accepted, well-established scale for measuring psychotic symptom severity. Conclusion We propose the use of the QPE to describe the phenomenology of PEs across modalities in Arabic speaking communities.

Measures of stepping volume and rate are common outputs from wearable devices, such as accelerometers. It has been proposed that biomedical technologies, including accelerometers and their algorithms, should undergo rigorous verification as well as analytical and clinical validation to demonstrate that they are fit for purpose. The aim of this study was to use the V3 framework to assess the analytical and clinical validity of a wrist-worn measurement system of stepping volume and rate, formed by the GENEActiv accelerometer and GENEAcount step counting algorithm. The analytical validity was assessed by measuring the level of agreement between the wrist-worn system and a thigh-worn system (activPAL), the reference measure. The clinical validity was assessed by establishing the prospective association between the changes in stepping volume and rate with changes in physical function (SPPB score). The agreement of the thigh-worn reference system and the wrist-worn system was excellent for total daily steps (CCC = 0.88, 95% CI 0.83–0.91) and moderate for walking steps and faster-paced walking steps (CCC = 0.61, 95% CI 0.53–0.68 and 0.55, 95% CI 0.46–0.64, respectively). A higher number of total steps and faster paced-walking steps was consistently associated with better physical function. After 24 months, an increase of 1000 daily faster-paced walking steps was associated with a clinically meaningful increase in physical function (0.53 SPPB score, 95% CI 0.32–0.74). We have validated a digital susceptibility/risk biomarker—pfSTEP—that identifies an associated risk of low physical function in community-dwelling older adults using a wrist-worn accelerometer and its accompanying open-source step counting algorithm. [ABSTRACT FROM AUTHOR]

Background: Psychotic experiences are reported in the general population. The Questionnaire for Psychotic Experiences (QPE) was created to test the phenomenological features of these experiences and compare them with those reported in patients with psychiatric and other medical conditions. The aim of this study was to test the psychometric properties of the Arabic version of the QPE. Methods: We recruited 50 patients with psychotic disorders from the Hamad Medical Hospital in Doha, Qatar. Patients underwent assessment over three sessions with trained interviewees using the Arabic versions of QPE, Positive and Negative Syndrome Scale (PANSS), Beck Depression Inventory (BDI), and the Global Assessment of Functioning Scale (GAF). Patients were also reassessed using the QPE and GAF after 14-days from the initial assessment in order to test for the stability of the scale. In this respect, this is the first study that assesses the test–retest reliability of the QPE. The psychometric properties including convergent validity, stability, and internal consistency met the benchmarked criteria. Results: Results confirmed that the Arabic version of QPE accurately measured the experiences of patients that were also reported using the PANSS, an internationally accepted, well-established scale for measuring psychotic symptom severity. Conclusion: We propose the use of the QPE to describe the phenomenology of PEs across modalities in Arabic speaking communities. [ABSTRACT FROM AUTHOR]

Despite great interest in Mind Wandering, a fully validated questionnaire has been lacking. The Four Factors of Mind Wandering (4FMW) Questionnaire, presented here, meets this demand. First, 80 items were judged for content validity by two panels of experts. Those items that survived this content validity assessment were then tested using exploratory and confirmatory factor analyses on two independent samples of young adults. The 16 resulting items were shown to cluster into four factors (i.e., Failure in social interaction, Failure in interaction with objects, Unawareness, and Inattention). The 4FMW questionnaire showed good reliability, robust structure, and acceptable goodness-of-fit indices, as well as good convergent validity with another Mind Wandering questionnaire. Importantly, the 4FMW questionnaire was able to discriminate between attention-deficit/hyperactivity disorder and obsessive–compulsive disorder symptoms. The 4FMW Questionnaire is a reliable and valid instrument for assessing mind wandering in the young adult population. [ABSTRACT FROM AUTHOR]

Objective The purpose of this study was to compare Quidel's rapid antigen test Sofia SARS antigen Fluorescent Immunoassay (FIA) (Sofia) with the real-time reverse transcription–polymerase chain reaction (rRT-PCR) test. Methods Two samples were taken from each test subject—1 for testing with the Sofia test and 1 for testing with the rRT-PCR test. In total, swabs were taken from 146 subjects who presented symptoms of infection (group 1) and 672 subjects who were tested regardless of symptoms (group 2). Results In group 1, the sensitivity of the antigen test was 90.0% and its specificity 97.5%. In group 2, however, the sensitivity of the antigen test was 81.4% and the specificity 98.9%. In addition to asymptomatic patients, false-negative results of rapid antigen tests also occurred in subjects with high threshold values (cycle threshold > 30). Conclusion Our results show that the Sofia test meets the standards for diagnostic tests according to the criteria of the World Health Organization, as they show high sensitivity and specificity, and perhaps most importantly, a high negative predictive value (> 95%). [ABSTRACT FROM AUTHOR]

Simple Summary: Cellular proliferation is a central determinant of breast cancer recurrence risk and response to chemotherapy. The discovery of the Ki-67 antibody by Dr. Johannes Gerdes in 1983, with the observation that Ki-67 immunohistochemical expression was only present in proliferating cells, opened the door for considerations about using Ki-67 immunohistochemical expression for the evaluation of breast cancer recurrence risk, as well as for the evaluation of how well patients with breast cancer might respond to chemotherapy. Unfortunately, the lack of consistently reproducible Ki-67 results between pathologists has limited the use of Ki-67 for these prognostic and predictive evaluations in routine clinical practice. We review how the use of Ki-67 in breast cancer has evolved over the past 40 years, with a summary of the present literature on Ki-67 in breast cancer, and a discussion on the future of Ki-67 as a prognostic and predictive marker for breast cancer in clinical practice. The 1983 discovery of a mouse monoclonal antibody—the Ki-67 antibody—that recognized a nuclear antigen present only in proliferating cells represented a seminal discovery for the pathologic assessment of cellular proliferation in breast cancer and other solid tumors. Cellular proliferation is a central determinant of prognosis and response to cytotoxic chemotherapy in patients with breast cancer, and since the discovery of the Ki-67 antibody, Ki-67 has evolved as an important biomarker with both prognostic and predictive potential in breast cancer. Although there is universal recognition among the international guideline recommendations of the value of Ki-67 in breast cancer, recommendations for the actual use of Ki-67 assays in the prognostic and predictive evaluation of breast cancer remain mixed, primarily due to the lack of assay standardization and inconsistent inter-observer and inter-laboratory reproducibility. The treatment of high-risk ER-positive/human epidermal growth factor receptor-2 (HER2) negative breast cancer with the recently FDA-approved drug abemaciclib relies on a quantitative assessment of Ki-67 expression in the treatment decision algorithm. This further reinforces the urgent need for standardization of Ki-67 antibody selection and staining interpretation, which will hopefully lead to multidisciplinary consensus on the use of Ki-67 as a prognostic and predictive marker in breast cancer. The goals of this review are to highlight the historical evolution of Ki-67 in breast cancer, summarize the present literature on Ki-67 in breast cancer, and discuss the evolving literature on the use of Ki-67 as a companion diagnostic biomarker in breast cancer, with consideration for the necessary changes required across pathology practices to help increase the reliability and widespread adoption of Ki-67 as a prognostic and predictive marker for breast cancer in clinical practice. [ABSTRACT FROM AUTHOR]

HepB LiveTest is a machine learning decision support system developed for the early detection of hepatitis B virus (HBV). However, there is a lack of evidence on its generalisability. In this study, we aimed to externally assess the clinical validity and portability of HepB LiveTest in predicting HBV infection among independent patient cohorts from Nigeria and Australia. The performance of HepB LiveTest was evaluated by constructing receiver operating characteristic curves and estimating the area under the curve. Delong’s method was used to estimate the 95% confidence interval (CI) of the area under the receiver-operating characteristic curve (AUROC). Compared to the Australian cohort, patients in the derivation cohort of HepB LiveTest and the hospital-based Nigerian cohort were younger (mean age, 45.5 years vs. 38.8 years vs. 40.8 years, respectively; p < 0.001) and had a higher incidence of HBV infection (1.9% vs. 69.4% vs. 57.3%). In the hospital-based Nigerian cohort, HepB LiveTest performed optimally with an AUROC of 0.94 (95% CI, 0.91–0.97). The model provided tailored predictions that ensured most cases of HBV infection did not go undetected. However, its discriminatory measure dropped to 0.60 (95% CI, 0.56–0.64) in the Australian cohort. These findings indicate that HepB LiveTest exhibits adequate cross-site transportability and clinical validity in the hospital-based Nigerian patient cohort but shows limited performance in the Australian cohort. Whilst HepB LiveTest holds promise for reducing HBV prevalence in underserved populations, caution is warranted when implementing the model in older populations, particularly in regions with low incidence of HBV infection.

Background: Molecular tests for thyroid nodules with indeterminate fine needle aspiration results are increasingly used in clinical practice; however, true diagnostic summaries of these tests are unknown. A systematic review and meta-analysis were completed to (1) evaluate the accuracy of commercially available molecular tests for malignancy in indeterminate thyroid nodules and (2) quantify biases and limitations in studies that validate those tests. Summary: PubMed, EMBASE, and Web of Science were systematically searched through July 2021. English language articles that reported original clinical validation attempts of molecular tests for indeterminate thyroid nodules were included if they reported counts of true-negative, true-positive, false-negative, and false-positive results. We performed screening and full-text review, followed by assessment of eight common biases and limitations, extraction of diagnostic and histopathological information, and meta-analysis of clinical validity using a bivariate linear mixed-effects model. Forty-nine studies were included. Meta-analysis of Afirma Gene expression classifiers (GEC; n = 38 studies) revealed a sensitivity of 0.92 (confidence interval: 0.90–0.94), specificity of 0.26 (0.20–0.32), negative likelihood ratio (LR−) of 0.32 (0.23–0.44), positive LR+ of 1.24 (1.15–1.35), and area under the curve (AUC) of 0.83 (0.74–0.89). Afirma Genomic Sequencing Classifier (GSC; n = 10) had a sensitivity of 0.94 (0.89–0.96), specificity of 0.38 (0.27–0.50), LR− of 0.18 (0.10–0.30), LR+ of 1.52 (1.28–1.87), and AUC of 0.91 (0.62–0.92). ThyroSeq v1 and v2 (n = 10) had a sensitivity of 0.86 (0.82–0.90), specificity of 0.74 (0.59–0.85), LR− of 0.19 (0.13–0.26), LR+ of 3.52 (2.08–5.92), and AUC of 0.86 (0.81–0.90). ThyroSeq v3 (n = 6) had a sensitivity of 0.92 (0.86–0.95), specificity of 0.41 (0.18–0.69), LR− of 0.24 (0.09–0.62), LR+ of 1.67 (1.09–2.98), and AUC of 0.90 (0.63–0.92). Fourteen percent of studies conducted a blinded histopathologic review of excised thyroid nodules, and 8% made the decision to go to surgery blind to molecular test results. Conclusions: Meta-analyses reveal a high diagnostic accuracy of molecular tests for thyroid nodule assessment of malignancy risk; however, these studies are subject to several limitations. Limitations and their potential clinical impacts must be addressed and, when feasible, adjusted for using valid statistical methodologies. [ABSTRACT FROM AUTHOR]

Background: Orthopedic surgeons use manual measurements, acetate templating, and dedicated software to determine the appropriate implant size for total knee arthroplasty (TKA). This study aimed to use deep learning (DL) to assist in deciding the femoral and tibial implant sizes without manual manipulation and to evaluate the clinical validity of the DL decision by comparing it with conventional manual procedures., Methods: Two types of DL were used to detect the femoral and tibial regions using the You Only Look Once algorithm model and to determine the implant size from the detected regions using convolutional neural network. An experienced surgeon predicted the implant size for 234 patient cases using manual procedures, and the DL model also predicted the implant sizes for the same cases., Results: The exact accuracies of the surgeon's template were 61.54% and 68.38% for predicting femoral and tibial implant sizes, respectively. Meanwhile, the proposed DL model reported exact accuracies of 89.32% and 90.60% for femoral and tibial implant sizes, respectively. The accuracy ± 1 levels of the surgeon and proposed DL model were 97.44% and 97.86%, respectively, for the femoral implant size and 98.72% for both the surgeon and proposed DL model for the tibial implant size., Conclusion: The observed differences and higher agreement levels achieved by the proposed DL model demonstrate its potential as a valuable tool in preoperative decision-making for TKA. By providing accurate predictions of implant size, the proposed DL model has the potential to optimize implant selection, leading to improved surgical outcomes., (© 2024. The Author(s).)

Introduction: Well-chosen biomarkers have the potential to increase the efficiency of clinical trials and drug discovery and should show good precision as well as clinical validity., Methods: We suggest measures that operationalize these criteria and describe a general approach that can be used for inference-based comparisons of biomarker performance. The methods are applied to measures obtained from structural magnetic resonance imaging (MRI) from individuals with mild dementia (n = 70) or mild cognitive impairment (MCI; n = 303) enrolled in the Alzheimer's Disease Neuroimaging Initiative., Results: Ventricular volume and hippocampal volume showed the best precision in detecting change over time in both individuals with MCI and with dementia. Differences in clinical validity varied by group., Discussion: The methodology presented provides a standardized framework for comparison of biomarkers across modalities and across different methods used to generate similar measures and will help in the search for the most promising biomarkers., Highlights: A framework for comparison of biomarkers on pre-defined criteria is presented. Criteria for comparison include precision in capturing change and clinical validity. Ventricular volume has high precision in change for both dementia and mild cognitive impairment (MCI) trials. Imaging measures' performance in clinical validity varies more for dementia than for MCI., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The aim of this study was to evaluate clinical validity of the S-1 dosage formula based on body surface area (BSA) and creatinine clearance (CLcr) to achieve the target area under the concentration–time curve of 5-FU, which we had developed and refined in each prospective pharmacokinetic study. Methods: The recommended dose determined by the refined formula was assessed using data of the SPIRITS (S-1 vs. S-1 plus cisplatin [SP]) and the G-SOX (SP vs. S-1 plus oxaliplatin [SOX]) trials. Nine hundred and thirty-eight patients in these trials were classified into three groups according to their actual S-1 starting doses compared with the recommended doses (under-dosed, recommended dose). Results: The patients in the under-dosed group in both trials showed similar tendencies: male, younger, higher BSA, and higher CLcr. The incidence of any grade neutropenia was significantly greater in the over-dosed group compared with the equal-dosed group in the S-1 and the SOX arms. The hazard ratios (HR) of overall survival (OS) (under-dosed vs. equal-dosed) were 1.361 (S-1 arm), 1.259 (SP arm) in the SPIRITS trial, and 1.381 (SOX arm), 0.999 (SP arm) in the G-SOX trial. Multivariate analysis in all the patients demonstrated that OS of the over-dosed group was equivalent (HR 1.002, 95% confidence interval [CI] 0.850–1.182, p = 0.980) and that of the under-dosed group was inferior (HR 1.267, 95% CI 1.005–1.597, p = 0.045) to the equal-dosed group. Conclusions: It is suggested that the refined S-1 dosage formula can recommend optimal dose in terms of safety and efficacy. [ABSTRACT FROM AUTHOR]

Although the rates of disease gene discovery have steadily increased with the expanding use of genome and exome sequencing by clinical and research laboratories, only ~16% of genes in the genome have confirmed disease associations. Here we describe our clinical laboratory's experience utilizing GeneMatcher, an online portal designed to promote disease gene discovery and data sharing. Since 2016, we submitted 246 candidates from 243 unique genes to GeneMatcher, of which 111 (45%) are now clinically characterized. Submissions meeting our candidate gene‐reporting criteria based on a scoring system using patient and molecular‐weighted evidence were significantly more likely to be characterized as of October 2021 versus genes that did not meet our clinical‐reporting criteria (p = 0.025). We reported relevant findings related to these newly characterized gene–disease associations in 477 probands. In 218 (46%) instances, we issued reclassifications after an initial negative or candidate gene (uncertain) report. We coauthored 104 publications delineating gene–disease relationships, including descriptions of new associations (60%), additional supportive evidence (13%), subsequent descriptive cohorts (23%), and phenotypic expansions (4%). Clinical laboratories are pivotal for disease gene discovery efforts and can screen phenotypes based on genotype matches, contact clinicians of relevant cases, and issue proactive reclassification reports. [ABSTRACT FROM AUTHOR]

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.

Background: The most significant biomarkers that are included in the Alzheimer's disease (AD) research framework are amyloid-β plaques deposition, p-tau, t-tau, and neurodegeneration.Although cerebrospinal fluid (CSF) biomarkers are included in the most recent AD research criteria, their use is increasing in the routine clinical practice and is applied also to the preclinical phases of AD, including mild cognitive impairment. The role of these biomarkers is still unclear concerning the preclinical stage of AD diagnosis, the CSF methodology, and the costs-benefits of the biomarkers' tests. The controversies regarding the use of biomarkers in the clinical practice are related to the concepts of analytical validity, clinical validity, and clinical utility and to the question of whether they are able to diagnose AD without the support of AD clinical phenotypes.Objective: The objective of the present work is to expose the strengths and weaknesses of the use of CSF biomarkers in the diagnosis of AD in a clinical context.Methods: We used PubMed as main source for articles published and the final reference list was generated on the basis of relevance to the topics covered in this work.Results: The use of CSF biomarkers for AD diagnosis is certainly important but its indication in routine clinical practice, especially for prodromal conditions, needs to be regulated and also contextualized considering the variety of possible clinical AD phenotypes.Conclusion: We suggest that the diagnosis of AD should be understood both as clinical and pathological. [ABSTRACT FROM AUTHOR]

Background: Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs.Objective and Rationale: In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes.Search Methods: We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'male infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org.Outcomes: The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes.Wider Implications: Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human male infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended. [ABSTRACT FROM AUTHOR]

Background: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment., Methods: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET., Results: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status., Discussion: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET., (© 2024 C2N Diagnostics LLC. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: Gene selection for genomic newborn screening (gNBS) underpins the validity, acceptability, and ethical application of this technology. Existing gNBS gene lists are highly variable despite being based on shared principles of gene-disease validity, treatability, and age of onset. This study aimed to curate a gNBS gene list that builds upon existing efforts and provide a core consensus list of gene-disease pairs assessed by multiple expert groups worldwide., Methods: Our multidisciplinary expert team curated a gene list using an open platform and multiple existing curated resources. We included severe treatable disorders with age of disease onset <5 years with established gene-disease associations and reliable variant detection. We compared the final list with published lists from 5 other gNBS projects to determine consensus genes and to identify areas of discrepancy., Results: We reviewed 1279 genes and 604 met our inclusion criteria. Metabolic conditions comprised the largest group (25%), followed by immunodeficiencies (21%) and endocrine disorders (15%). We identified 55 consensus genes included by all 6 gNBS research projects. Common reasons for discrepancy included variable definitions of treatability and strength of gene-disease association., Conclusion: We have identified a consensus gene list for gNBS that can be used as a basis for systematic harmonization efforts internationally., Competing Interests: Conflict of Interest The authors declare no conflicts of interest. Ethics Declaration The project has received ethics approval from the Royal Children’s Hospital Melbourne Research Ethics Committee: HREC/91500/RCHM-2023., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

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. [ABSTRACT FROM AUTHOR]

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 clínicamente de forma preliminar el diagnóstico enfermero NANDA‐I duelo en caso de pérdida perinatal. MÉTODOS: Estudio descriptivo transversal usando el modelo de Fehring. RESULTADOS: El índice de validez clínica global del diagnóstico fue de 0.15. Se validaron únicamente cuatro características definitorias y cinco manifestaciones identificadas en la literatura. CONCLUSIONES: Se considera que la variabilidad de las manifestaciones presentadas por los participantes actuó en detrimento del índice de validación clínica global. IMPLICACIONES PARA LA PRÁCTICA ENFERMERA: La validez clínica del diagnóstico no pudo ser corroborada por los resultados preliminares de este estudio y, por tanto, se necesita investigación adicional para terminar la capacidad de este diagnóstico para adaptarse a las situaciones de pérdidas perinatales en contexto reales. Se han propuesto a NANDA‐I algunas manifestaciones para que sean incluidas como Características Definitorias del diagnóstico enfermero Duelo. [ABSTRACT FROM AUTHOR]

Aim: 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 = <.001) were found in more advanced stages of disease. Moreover, patients with FEP and a DUP longer than 1 year showed significantly more severe negative symptoms (U = 314 000, P =.015) compared to patients with a DUP shorter than 1 year. Conclusions: The present study found supporting evidence for the clinical validity of the staging model in schizophrenia spectrum disorders. In addition, we found support for refining the stage "first episode" with information concerning the DUP. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Purpose To create a Dutch translated short version of the Breast Cancer Treatment Outcome Scale (BCTOS) and validate it in patients who have completed both breast conserving surgery and adjuvant radiotherapy. Methods The BCTOS consists of items comparing the treated with the untreated breast. After forward and backward translation, we tested the BCTOS-12 plus 5 additional items. Two-hundred breast cancer patients treated with breast conserving therapy (BCT) between January 2016 and December 2017, were asked to complete the BCTOS items twice with a 2 week interval. The EORTC QLQ-BR23 breast and arm symptoms subscales were completed once in parallel. Feasibility was assessed by missing or non-unique answer rates and content validity with floor and ceiling effect analysis. Construct validity was evaluated with 1) principal component analysis (PCA) 2) convergent validity and 3) known groups comparison (clinical validity differentiating between patients with and without locoregional side effects). From all potential items with good feasibility, content and construct validity, items were selected for the Dutch BCTOS based on clinical validity. The relation to the EORTC QLQ-BR23 subscales and reliability was tested for the new Dutch BCTOS. Results Hundred and one of 200 (50.5%) approached patients participated in this study, with follow-up after surgery ranging from 5 to 29 months. Feasibility was high (1.5% missing answers). Content validity testing showed a floor effect > 20% in all 17 items. PCA showed that all items loaded well (> 0.4) into the assigned subscale and revealed two distinct subscales: cosmesis and function. Based on clinical validity, item “breast shape” was replaced by “breast elevation/position” and “overall skin appearance”. Very good clinical validity (Cohen’s d = 1.38) was found for the new Dutch BCTOS-13. Correlation to the EORTC QLQ-BR23 subscales was high (ICC = 0.65–0.85) for both subscales. Test-retest reliability (Cohen’s d = 0.105) and internal consistency (Cronbach’s α =0.90) were excellent. Conclusions Psychometric evaluation of a newly developed Dutch BCTOS-13 questionnaire in BCT patients showed excellent results, that were slightly better than the original BCTOS-22 and the shortened BCTOS-12. The good clinical validity makes the BCTOS-13 a useful tool to identify patients with unfavourable cosmetic and functional outcomes, requiring specific attention.

Abstract Background Absence of context-specific clinically validated cut-off values for assessing burnout as a dichotomous phenomenon has hindered the progress of student burnout research with regard to quantifying the magnitude of the problem. Hence, the present study was aimed at developing clinically validated cut-off values and evaluating the diagnostic accuracy of the Sinhala translation of the 15-item Maslach Burnout Inventory-Student Survey (MBI-SS) in assessing burnout among collegiate cycle students in Sri Lanka. Methods This prospective validation study was conducted among 194 grade thirteen students in the Kurunegala district, Sri Lanka. Clinically validated cut-off values for the subscale scores of the MBI-SS test was developed by computing ROC curves, using the clinical diagnosis made by the Consultant Psychiatrist as the reference standard. Diagnostic accuracy of the MBI-SS test results based on “exhaustion+ 1” criterion was assessed comparing with the results of the clinical diagnosis. Results The clinically validated cut-off values for the exhaustion, cynicism and reduced professional efficacy subscale scores were 12.5, 7.5 and 10.5 for the respectively. The sensitivity, specificity, positive and negative predictive values of the Sinhala translation of the 15-item MBI-SS were 91.9% (95% CI = 82.5–96.5%), 93.2% (95% CI = 87.5–96.4%), 86.4% (95% CI = 76.1–92.7%) and 96.1% (95% CI = 91.2–98.3%) respectively. The positive and negative likelihood ratios were 13.48 (95% CI = 7.15–25.44) and 0.09 (95% CI = 0.04–0.20) respectively. Conclusions By using the clinically validated cut-off values for the subscale scores and based on the “exhaustion + 1” criterion, the Sinhala translation of the 15-item MBI-SS could be effectively used as a screening tool to assess burnout among collegiate cycle students. The study findings broaden the global evidence base pertaining to validated cut-off values of the MBI-SS.

Purpose: To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases., Methods: We prospectively enrolled 297 probands who met eligibility criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests., Results: Laboratories reported 105 molecular diagnoses and 165 uncertain results in known and novel genes. Of these, clinicians interpreted 102 of 105 (97%) molecular diagnoses and 6 of 165 (4%) uncertain results as clinical-molecular diagnoses. The 108 clinical-molecular diagnoses were in 104 families (35% diagnostic yield). Each eligibility criteria resulted in diagnostic yields of 30% to 40%, and higher yields were achieved when >2 eligibility criteria were met (up to 45%). Hypothetical tests would have identified 61% of clinical-molecular diagnoses., Conclusion: We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2023. Published by Elsevier Inc.)

Clinical guidelines consider expanded carrier screening (ECS) to be an acceptable method of carrier screening. However, broader guideline support and payer adoption require evidence for associations between the genes on ECS panels and the conditions for which they aim to identify carriers. We applied a standardized framework for evaluation of gene‐disease association to assess the clinical validity of conditions screened by ECS panels. The Clinical Genome Resource (ClinGen) gene curation framework was used to assess genetic and experimental evidence of associations between 208 genes and conditions screened on two commercial ECS panels. Twenty‐one conditions were previously classified by ClinGen, and the remaining 187 were evaluated by curation teams at two laboratories. To ensure consistent application of the framework across the laboratories, concordance was evaluated on a subset of conditions. All 208 evaluated conditions met the evidence threshold for supporting a gene‐disease association. Furthermore, 203 of 208 (98%) achieved the strongest ("Definitive") level of gene‐disease association. All conditions evaluated by both commercial laboratories were similarly classified. Assessment using the ClinGen standardized framework revealed strong evidence of gene‐disease association for conditions on two ECS panels. This result establishes the disease‐level clinical validity of the panels considered herein. [ABSTRACT FROM AUTHOR]

This paper is based on the keynote presentation for the biennial meeting of the International Society for Research on Child and Adolescent Psychopathology (ISRCAP) in Los Angeles, California. The topic was purposively selected to raise awareness of how the measurement of child behavioral health care quality at the national level, and corresponding standards for reliability and clinical validity, substantially differ from those traditionally applied to the measurement of child psychopathology. Under a federal mandate, an initial Core Set of quality measures for children was created for voluntary reporting by State Medicaid agencies. The four national child behavioral health quality measures in the 2019 Child Core Set encompass timeliness of care, vary by child age range, and two different types of psychotropic medication treatments. Measures are described and implications for data interpretation are provided. Findings are summarized from: 1) a systematic literature review; 2) State adherence rates; and 3) ten-year national trends in adherence rates by health plan type. Scientific evidence supporting the clinical validity of the measures is scarce, statewide adherence rates widely vary, and improvement over time has been modest. Nevertheless, State Medicaid agencies will be mandated to report measure adherence rates beginning in 2024. Together, these findings stimulate recommendations for health policies to allocate additional resources for data infrastructure to monitor child mental health care quality and identify areas for future research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: The Structured Clinical Interview for the DSM is one of the most used diagnostic instruments in clinical research worldwide. The current Clinician Version of the instrument (SCID‐5‐CV) has not yet been assessed in respect to its psychometric qualities. We aimed to assess the clinical validity and different reliability indicators (interrater test–retest, joint interview, face‐to‐face vs telephone application) of the SCID‐5‐CV in a large sample of 180 non‐prototypical and psychiatric patients based on interviews conducted by raters with different levels of clinical experience. Methods: The SCID‐5‐CV was administered face‐to‐face and by telephone by 12 psychiatrists/psychologists who took turns as raters and observers. Clinical diagnoses were established according to DSM‐5 criteria and the longitudinal, expert, all data (LEAD) procedure. We calculated the percentage of agreement, diagnostic sensitivity and specificity, and the level of agreement (kappa) for diagnostic categories and specific diagnoses. Results: The percentage of positive agreement between the interview and clinical diagnoses ranged between 73% and 97% and the diagnostic sensitivity/specificity were >0.70. In the joint interview, the levels of positive agreement were high (>75%) and kappa levels were >0.70 for most diagnoses. The values were less expressive, but still adequate, for interrater test–retest interviews. Conclusion: The SCID‐5‐CV presented excellent reliability and high specificity as assessed with different methods. The clinical validity of the instrument was also confirmed, which supports its use in daily clinical practice. We highlight the adequacy of the instrument to be used via telephone and the need for careful use by professionals with little experience in psychiatric clinical practice. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Multigene panel testing for breast and ovarian cancer predisposition diagnosis is a useful tool as it makes possible to sequence a considerable number of genes in a large number of individuals. More than 200 different multigene panels in which the two major BRCA1 and BRCA2 breast cancer predisposing genes are included are proposed by public or commercial laboratories. We review the clinical validity and clinical utility of the 26 genes most oftenly included in these panels. Because clinical validity and utility are not established for all genes and due to the heterogeneity of tumour risk levels, there is a substantial difficulty in the routine use of multigene panels if management guidelines and recommendations for testing relatives are not previously defined for each gene. Besides, the classification of variant of unknown significance (VUS) is a particular limitation and challenge. Efforts to classify VUSs and also to identify factors that modify cancer risks are now needed to produce personalised risk estimates. The complexity of information, the capacity to come back to patients when VUS are re-classified as pathogenic, and the expected large increase in the number of individuals to be tested especially when the aim of multigene panel testing is not only prevention but also treatment are challenging both for physicians and patients. Quality of tests, interpretation of results, information and accompaniment of patients must be at the heart of the guidelines of multigene panel testing. • Multigene panel allows to sequence a high number of genes in numerous individuals. • Management and relative testing guidelines need to be defined for each gene. • Variant classification is a challenge amplified by NGS. • Quality of tests, information and accompaniment of patients are testing guidelines. • Tumour DNA is the native DNA of the patient!. [ABSTRACT FROM AUTHOR]

Study Question: Which genes are confidently linked to human monogenic male infertility?Summary Answer: Our systematic literature search and clinical validity assessment reveals that a total of 78 genes are currently confidently linked to 92 human male infertility phenotypes.What Is Known Already: The discovery of novel male infertility genes is rapidly accelerating with the availability of next-generating sequencing methods, but the quality of evidence for gene-disease relationships varies greatly. In order to improve genetic research, diagnostics and counseling, there is a need for an evidence-based overview of the currently known genes.Study Design, Size, Duration: We performed a systematic literature search and evidence assessment for all publications in Pubmed until December 2018 covering genetic causes of male infertility and/or defective male genitourinary development.Participants/materials, Setting, Methods: Two independent reviewers conducted the literature search and included papers on the monogenic causes of human male infertility and excluded papers on genetic association or risk factors, karyotype anomalies and/or copy number variations affecting multiple genes. Next, the quality and the extent of all evidence supporting selected genes was weighed by a standardized scoring method and used to determine the clinical validity of each gene-disease relationship as expressed by the following six categories: no evidence, limited, moderate, strong, definitive or unable to classify.Main Results and the Role Of Chance: From a total of 23 526 records, we included 1337 publications about monogenic causes of male infertility leading to a list of 521 gene-disease relationships. The clinical validity of these gene-disease relationships varied widely and ranged from definitive (n = 38) to strong (n = 22), moderate (n = 32), limited (n = 93) or no evidence (n = 160). A total of 176 gene-disease relationships could not be classified because our scoring method was not suitable.Large Scale Data: Not applicable.Limitations, Reasons For Caution: Our literature search was limited to Pubmed.Wider Implications Of the Findings: The comprehensive overview will aid researchers and clinicians in the field to establish gene lists for diagnostic screening using validated gene-disease criteria and help to identify gaps in our knowledge of male infertility. For future studies, the authors discuss the relevant and important international guidelines regarding research related to gene discovery and provide specific recommendations for the field of male infertility.Study Funding/competing Interest(s): This work was supported by a VICI grant from The Netherlands Organization for Scientific Research (918-15-667 to J.A.V.), the Royal Society, and Wolfson Foundation (WM160091 to J.A.V.) as well as an investigator award in science from the Wellcome Trust (209451 to J.A.V.).Prospero Registration Number: None. [ABSTRACT FROM AUTHOR]

Background and aims: Internet Gaming Disorder (IGD) and other Internet-related disorders (IRDs) have become growing health concerns in our today's lives. Based on defined diagnostic criteria, IGD has been recognized as a condition for further research in the DSM-5; however, other IRDs have been excluded. Since the release of the DSM-5, representativeness and appropriateness of the nine diagnostic criteria have been debated. Although some first evidence has been published to evaluate these criteria, our knowledge is still limited. Thus, the purpose of this study was to provide data on the clinical validity of the DSM-5 criteria for IGD and other types of IRD. We were also interested in examining the additional diagnostic validity of craving that is currently not being considered in the DSM-5. Methods: Analyses on a sample of n = 166 treatment seekers for IRDs were performed. The clinician's diagnosis was used as a main reference for determining the DSM criteria's diagnostic performance. Secondary criteria (depression and anxiety) were defined as indicators for the construct validity. Results: The overall diagnostic accuracy ranged between 76.6% for deceiving and 92% for loss of control and craving. Considerable differences occurred in the degree of sensitivity and specificity between the single criteria. No particular differences were found for the applicability of the criteria to other forms of IRDs. Discussion and conclusions: Our results confirm the validity of the DSM criteria. However, the diagnostic utility of the criterion escaping aversive moods is critically discussed. Considering craving as an additional diagnostic indicator might be recommendable. [ABSTRACT FROM AUTHOR]

Introduction: Reimbursement of amyloid–positron emission tomography (PET) is lagging due to the lack of definitive evidence on its clinical utility and cost‐effectiveness. The Amyloid Imaging to Prevent Alzheimer's Disease–Diagnostic and Patient Management Study (AMYPAD‐DPMS) is designed to fill this gap. Methods: AMYPAD‐DPMS is a phase 4, multicenter, prospective, randomized controlled study. Nine hundred patients with subjective cognitive decline plus, mild cognitive impairment, and dementia possibly due to Alzheimer's disease will be randomized to ARM1, amyloid‐PET performed early in the diagnostic workup; ARM2, amyloid‐PET performed after 8 months; and ARM3, amyloid‐PET performed whenever the physician chooses to do so. Endpoints: The primary endpoint is the difference between ARM1 and ARM2 in the proportion of patients receiving a very‐high‐confidence etiologic diagnosis after 3 months. Secondary endpoints address diagnosis and diagnostic confidence, diagnostic/therapeutic management, health economics and patient‐related outcomes, and methods for image quantitation. Expected Impacts: AMYPAD‐DPMS will supply physicians and health care payers with real‐world data to plan management decisions. [ABSTRACT FROM AUTHOR]

Background: Diagnostic test accuracy (DTA) systematic reviews (SRs) characterize a test's potential for diagnostic quality and safety. However, interpreting DTA measures in the context of SRs is challenging. Further, some evidence grading methods (e.g. Centers for Disease Control and Prevention, Division of Laboratory Systems Laboratory Medicine Best Practices method) require determination of qualitative effect size ratings as a contributor to practice recommendations. This paper describes a recently developed effect size rating approach for assessing a DTA evidence base. Methods: A likelihood ratio scatter matrix will plot positive and negative likelihood ratio pairings for DTA studies. Pairings are graphed as single point estimates with confidence intervals, positioned in one of four quadrants derived from established thresholds for test clinical validity. These quadrants support defensible judgments on "substantial", "moderate", or "minimal" effect size ratings for each plotted study. The approach is flexible in relation to a priori determinations of the relative clinical importance of false positive and false negative test results. Results and conclusions: This qualitative effect size rating approach was operationalized in a recent SR that assessed effectiveness of test practices for the diagnosis of Clostridium difficile. Relevance of this approach to other methods of grading evidence, and efforts to measure diagnostic quality and safety are described. Limitations of the approach arise from understanding that a diagnostic test is not an isolated element in the diagnostic process, but provides information in clinical context towards diagnostic quality and safety. [ABSTRACT FROM AUTHOR]

The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (a) precise phenotype definitions within existing disease and phenotype ontologies; (b) consideration of when epilepsy should be curated as a distinct disease entity; (c) strategies for gene selection; and (d) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted toward an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy‐associated genes is feasible and suggest epilepsy‐specific conventions, laying the groundwork for a curation process of all major epilepsy‐associated genes. Epilepsy is emerging as a frequent indication for diagnostic genetic testing. The ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting the domain of traditional clinical epileptology and the rapidly evolving area of diagnostic genetic testing. We identify precise phenotype definitions and phenotypic boundaries, gene selection strategies, and rules functional models for seizure disorders as critical components of the gene curation process. We demonstrate that curation for epilepsy‐associated genes is feasible and suggest epilepsy‐specific conventions. [ABSTRACT FROM AUTHOR]

In order for ClinGen to maintain up‐to‐date gene‐disease clinical validity classifications for use by clinicians and clinical laboratories, an appropriate timeline for reevaluating curated gene‐disease associations will need to be determined. To provide guidance on how often a gene‐disease association should be recurated, a retrospective analysis of 30 gene curations was performed. Curations were simulated at one‐year intervals starting with the year of the first publication to assert disease‐causing variants in the gene to observe trends in the classification over time, as well as factors that influenced changes in classification. On average, gene‐disease associations spent the least amount of time in the "Moderate" classification before progressing to "Strong" or "Definitive." In contrast, gene‐disease associations that spent five or more years in the "Limited" classification were most likely to remain "Limited" or become "Disputed/Refuted." Large population datasets contributed to the reclassification of several gene‐disease associations from "Limited" to "Disputed/Refuted." Finally, recent advancements in sequencing technology correlated with an increase in the quantity of case‐level evidence that was curated per paper. This study provided a number of key points to consider when determining how often to recurate a gene‐disease association. Maintaining the most current ClinGen gene‐disease clinical validity classifications requires an appropriate timeline for re‐evaluating curated gene‐disease associations. In order to provide guidance on how often a gene‐disease association should be re‐evaluated, a retrospective analysis of 30 gene curations was performed at one‐year intervals to identify trends in the classification over time and factors that influenced changes in classification. This study provides key consideration points for determining the most effective timeline for re‐evaluating gene‐disease associations. [ABSTRACT FROM AUTHOR]

Intolerance of Uncertainty is a fundamental transdiagnostic personality construct hierarchically organized with a core general factor underlying diverse clinical manifestations. The current study evaluated the construct validity of the Intolerance of Uncertainty Inventory, a two-part scale separately assessing a unitary Intolerance of Uncertainty disposition to consider uncertainties to be unacceptable and threatening (Part A) and the consequences of such disposition, regarding experiential avoidance, chronic doubt, overestimation of threat, worrying, control of uncertain situations, and seeking reassurance (Part B). Community members (N = 1046; Mean age = 36.69 ± 12.31 years; 61% females) completed the Intolerance of Uncertainty Inventory with the Beck Depression Inventory-II and the State-Trait Anxiety Inventory. Part A demonstrated a robust unidimensional structure and an excellent convergent validity with Part B. A bifactor model was the best fitting model for Part B. Based on these results, we compared the hierarchical factor scores with summated ratings clinical proxy groups reporting anxiety and depression symptoms. Summated rating scores were associated with both depression and anxiety and proportionally increased with the co-occurrence of depressive and anxious symptoms. By contrast, hierarchical scores were useful to detect which facets mostly separated between for depression and anxiety groups. In sum, Part A was a reliable and valid transdiagnostic measure of Intolerance of Uncertainty. The Part B was arguably more useful for assessing clinical manifestations of Intolerance of Uncertainty for specific disorders, provided that hierarchical scores are used. Overall, our study suggest that clinical assessments might need to shift toward hierarchical factor scores.