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Background: Ambulant biofeedback devices can be used to provide real-time feedback for trauma patients on weight-bearing regimes. The devices also enable prescribing clinicians to monitor and train patients? level of weight-bearing. However, there is limited evidence regarding the feasibility of use of such devices in controlling weight-bearing, and their full potential remains to be elucidated. Objective: To investigate the feasibility of using ambulant biofeedback training devices to improve compliance with weight-bearing regimes in trauma patients with lower extremity fractures. Methods: A literature review of the feasibility and clinical validity of ambulant biofeedback devices. Results: Three clinically validated biofeedback devices were found feasible for use in monitoring the compliance of patients who have lower extremity fractures with different weight-bearing regimes. Conclusion: Further information about the feasibility and clinical validity of biofeedback training devices is nee-ded in order to optimize weight-bearing instructions for patients.

Aims: The aim of this study was to assess whether the culotte technique could be improved by an additional kissing dilation prior to main branch (MB) stenting. Methods and results: Double-kissing (DK) culotte was compared to the culotte and DK-crush techniques in a bench model (n=24). Results were evaluated for stent apposition, luminal opening and flow dynamics. The total procedure duration of DK-culotte was 18.3±3.4 minutes, significantly lower than for DK-crush (24.3±5.7 min; p=0.015), but similar to culotte (21.6±5.9 min, p=0.104). In DK-culotte the overall rate of moderate (200-500 μm) and significant (>500 μm) malapposition was 2.1±1.9% and 0.4±0.2%, similar as compared to culotte (3.7±3.8%, p=0.459 and 1.0±1.0%, p=0.517, respectively), and lower as compared to DK-crush (8.1±2.5%, p

BACKGROUND: Omics technologies, enabling the measurements of genes (genomics), mRNA (transcriptomics), proteins (proteomics) and metabolites (metabolomics), are valuable tools for personalized decision-making. We aimed to identify the existing value assessment frameworks used by health technology assessment (HTA) doers for the evaluation of omics technologies through a systematic review. METHODS: PubMed, Scopus, Embase and Web of Science databases were searched to retrieve potential eligible articles published until 31 May 2020 in English. Additionally, through a desk research in HTA agencies' repositories, we retrieved the published reports on the practical use of these frameworks. RESULTS: Twenty-three articles were included in the systematic review. Twenty-two frameworks, which addressed genetic and/or genomic technologies, were described. Most of them derived from the ACCE framework and evaluated the domains of analytical validity, clinical validity and clinical utility. We retrieved forty-five reports, which mainly addressed the commercial transcriptomic prognostics and next generation sequencing, and evaluated clinical effectiveness, economic aspects, and description and technical characteristics. CONCLUSIONS: A value assessment framework for the HTA evaluation of omics technologies is not standardized and accepted, yet. Our work reports that the most evaluated domains are analytical validity, clinical validity and clinical utility and economic aspects. ispartof: INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH vol:17 issue:21 ispartof: location:Switzerland status: published

Цель. Оценить внутреннюю согласованность, надежность повторного тестирования и клиническую достоверность русской версии сокращенного опросника Индекс изменения голоса – 10 (Voice Handicap Index (VHI)-10). Материалы и методы. Проспективное обсервационное исследование. Оригинальная английская версия опросника VHI-10 была переведена на русский язык двумя независимыми исследователями (профессиональные переводчики). Окончательная русскоязычная версия (VHI-10рус) была сформулирована третьим исследователем (врач-оториноларинголог) на основе двух указанных переводов, а затем обратно переведена на английский язык. В исследо-вание был включен 181 участник. 91 пациент был разделен на группы в соответствии с формой дисфонии: 65 (71,4%) – функциональная и 26 (28,6%) – органическая дисфония (из которых у 8 (8,8%) выявлены воспалительные, у 7 (7,7%) структурные и у 11 (12,1%) неврологические изменения гортани). Контрольную группу составили 90 человек без нарушений голоса. Внутренняя согласованность (альфа-коэффициент Кронбаха, α), надежность повторного тестирования (внутриклассовый коэффициент корреляции (ICC)) VHI-10, сравнение показателей VHI-10 исследуемой и контрольной групп (U-критерий Манна – Уитни; критерий Краскела – Уоллиса) и корреляция с общей тяжестью дисфонии (коэффициент ранговой корреляции Спирмена, ρ) были рассчитаны. Результаты. В группе пациентов мы наблюдали отличную внутреннюю согласованность для VHI-10рус (α=0,95) и хорошую внутреннюю согласованность для всех подшкал VHI-10рус: физической (α=0,88), функциональной (α=0,88) и эмоциональной (α=0,88). Внутриклассовый коэффициент корреляции (ICC) указывает на высокую надежность повторного тестирования для пациентов (0,99) и контроля (0,84). Средние общие значения по 10 пунктам у участников с дисфонией были статистически выше, чем в контрольной группе (P, Purpose. To evaluate the internal consistency, retesting reliability, and clinical validity of the Russian version of the Voice Handicap Index (VHI)-10. Materials and methods. There was conducted a prospective observational study. The English version of the VHI-10 questionnaire was translated into Russian by two independent researchers (professional translators). The final Russian version (VHI-10rus) was formulated by the third researcher (ENT specialist) on the base of these two translations, and then translated back into English. The study included 181 participants; 91 patients were divided into groups, according to the form of dysphonia: 65 patients (71.4%) with functional one and 26 patients with organic one (8 patients (8.8%) had inflammatory laryngeal changes, 7 patients (7.7%) – structural ones, and 11 patients (12.1%) – neurological ones). The control group included 90 people without voice disorders and laryngeal abnormalities. Internal consistency (Cronbach alpha coefficient, α), reliability of retesting (intraclass correlation coefficient (ICC)) of VHI-10, comparison of VHI-10 values in the study group and control group (Mann – Whitney U-test; Kruskal – Wallis test), and correlation of the severity of dysphonia (Spearman’s rank correlation coefficient, ρ) were analyzed. Results. In the group of patients, we observed excellent internal consistency for the VHI-10rus (α=0.95) and good internal consistency for all subscales of the VHI-10rus: physical (α=0.88), functional (α=0.88) and emotional (α=0.88). The intraclass correlation coefficient (ICC) indicated the retest reliability of patients (0.99) and the control group (0.84). The average total scores of 10 items in dysphonic participants were significantly higher than in controls (P0.001). The correlation was found in VHI-10 in various patient groups and in the control group (Spearman’s correlation coefficient: functional – 0.942; inflammatory – 0.756; neurological – 0.888; structural – 0.982; control – 0.882). Conclusion. The Russian VHI-10 questionnaire is a useful tool for evaluating vocal changes in patients with dysphonia. In addition to objective examinations (acoustic and aerodynamic voice analysis), the VHI-10rus questionnaire lets to perform a complete clinical and functional assessment of voice in patients with dysphonia., Оториноларингология. Восточная Европа, Выпуск 3 2020

This commentary focuses on Lacan’s discussion of the clinical relevance of the Ego-Ideal and the Ideal Ego, as well as their relationship to narcissism in the XXIII session of Seminar VIII. From the main threads explored by Jacques Lacan along with a viable tension between philosophical and psychoanalytic arguments, this commentary provides insights and grounds to consider the exploration of the thinker. The commentary underlines three main subsets of Lacan’s discussion: (1) The psychoanalysts and their crowd; (2) Paradoxes of transference; and, (3) The place of the psychoanalyst; aiming at a better refinement of the French psychoanalyst concerns surrounding transference, its clinical validity and importance.

Objectives To investigate the clinical validity of self-rated oral health among older New Zealanders in aged residential care. Material and methods A national survey of oral health in aged residential care was carried out throughout New Zealand. Self-rated oral health was measured using Locker's global item and clinical examinations carried out by calibrated examiners. Analyses used survey weights. Results Consistent gradients were observed across the self-rated oral health categories in the mean number of decayed teeth (whether coronal or root surface caries), mean number of filled teeth (albeit in the opposite direction), and in the mean number of fillings needed. Consistent gradients were also seen in the same categories when comparing the current oral health status to their oral health status a year previous. No gradients in periodontal status were apparent. Conclusions The older population in aged residential care can validly self-rate their oral health, although further investigation of periodontal status is warranted.

BACKGROUND Pathogen inactivation (PI) techniques for platelet concentrates (PCs) are one of the latest innovations to improve blood safety and reduce the risk of transfusion-transmitted infections (TTIs). An impaired function and in vivo recovery of platelets as well as an increased PC demand are concerns regarding these techniques. The intent of this study was to evaluate the hemostatic effect of PCs treated with the Intercept™ System by thromboelastometry (TEM) and to assess the clinical validity of its results in comparison to post-transfusion increase (PTI) and corrected count increment (CCI). STUDY-DESIGN AND METHODS This prospective-observational study included 47 patients (m:f = 25:22; median age: 54 years [21-70]) of our Bone Marrow Transplantation unit with hemato-oncological malignancies transfused with Intercept™-treated PCs. Serial TEM measurements were performed just before and 1 hour after PC transfusion and were analyzed for their correlation with PTI and CCI as well as for clinical variables. RESULTS The majority of our patients had received a hematopoietic stem cell transplantation (HSCT) (n = 41; 87%). In median 9 (1-50) PCs were transfused. Serial TEM, PTI, and CCI measurements were available for 150 transfusion episodes. The median platelet dose transfused was 2.65 × 1011 /unit (1.8-6). The median CCI was 9.250 (0-28.000). We observed a significant improvement in TEM parameters (p

Background The development and application of clinical prediction models using machine learning in clinical decision support systems is attracting increasing attention. Objective The aims of this study were to develop a prediction model for cardiac arrest in the emergency department (ED) using machine learning and sequential characteristics and to validate its clinical usefulness. Methods This retrospective study was conducted with ED patients at a tertiary academic hospital who suffered cardiac arrest. To resolve the class imbalance problem, sampling was performed using propensity score matching. The data set was chronologically allocated to a development cohort (years 2013 to 2016) and a validation cohort (year 2017). We trained three machine learning algorithms with repeated 10-fold cross-validation. Results The main performance parameters were the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). The random forest algorithm (AUROC 0.97; AUPRC 0.86) outperformed the recurrent neural network (AUROC 0.95; AUPRC 0.82) and the logistic regression algorithm (AUROC 0.92; AUPRC=0.72). The performance of the model was maintained over time, with the AUROC remaining at least 80% across the monitored time points during the 24 hours before event occurrence. Conclusions We developed a prediction model of cardiac arrest in the ED using machine learning and sequential characteristics. The model was validated for clinical usefulness by chronological visualization focused on clinical usability.

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.

Introduction Guidelines recommend indexing measurements of left ventricle (LV) size to body surface area (BSA) to improve clinical validity. We sought to highlight the potential impact of misclassifying LV size in patients if indexing is not performed. Methods We reviewed the reports of all trans-thoracic echocardiograms performed at a large tertiary centre for cardiology and compared proportions of patients with LV dilatation based on LV internal diastolic dimension (LVIDd) > 5.8 cm (male), >5.2 cm (female) or indexed (Dubois) LVIDd > 3.0cm/m2 (male), > 3.1cm/m2 (female). We also identified all reports with a diagnosis of moderate-severe or severe aortic regurgitation and compared proportions of patients with LV dilatation that would reach the threshold for surgical intervention when indexed and non-indexed values are used. Results 20397 echocardiogram reports were reviewed. LV dilatation was present in 2821 (13.8%) based on non-indexed LVIDd compared to 2083 (10.2%) using indexed LVDD. After indexing for BSA 2202 (10.8%) patients changed category: 1470 (7.2%) patients deemed to have a dilated LV based on LVIDd were reclassified as normal, whereas 732 (3.6%) patients deemed to have a normal sized LV were reclassified as dilated when LVIDd was indexed. Reports of 71 patients with moderate-severe or severe aortic regurgitation were reviewed. 5 (7.0%) had a LV internal systolic dimension (LVIDs) >5cm meeting criteria to consider surgery. When indexed to BSA, 15 (21.1%) had indexed LVIDs >2.5cm/m2 with 11 (15.5%) changing from normal LVIDs to dilated LVIDs when indexed. Conclusion Indexing left ventricular dimensions results in reclassification of 10.8% of patients, which could have implications on clinical management decisions. Furthermore, up to 15.5% of patients with aortic regurgitation may transition from non-dilated to dilated LVIDs when indexed values are used and so impact on timing of surgical referral. Uncorrected and BSA corrected quantitative measurements should be available on all echocardiogram reports. Conflict of Interest None

Introduction: Over time, the management of rectal cancer has undoubtedly evolved with the use of neoadjuvant radiochemotherapy. Material and method: The P.I.C.O.S guidelines were used to structure the questions and the research topic as to attain clinical validity. The results of the research were filtered in accordance with the PRISMA checklist. Results: We identified 42 papers. After screening 27 papers were used to complete the analysis. Discussion: There is an increased interest towards the non-operative management of rectal cancer, as up to 25% of patients with preoperative radiochemotherapy have demonstrated complete pathological response (absence of tumor cells on the operative specimens). This information leads to the tantalizing idea that in some cases, surgery can be avoided. Unfortunately, there is a lack of quality data to support this view. Due to increased interest in this subject, an international database in which patients with w w therapy can be enrolled and monitored. Up to now, the database contains over 900 patients. Also, quality prospective trials are emerging. Conclusion: Even with all these recent efforts, the wide-use of this therapy is precluded due to the absence of a standardized evaluation of these patients in the follow-up period.

There is currently no oversight for canine clinical genetic testing laboratories. We published an initial set of standards and guidelines with the goal of providing a basis for which canine testing laboratories could evaluate their quality assurance programs. To further those standards and guidelines, we have developed a checklist that can be used as a self-evaluation to identify gaps in their programs for continual quality improvement over time. Because there is currently no organization willing to oversee an external proficiency program, the checklist provides the first step toward an internal, self-assessment that can be used periodically to monitor improvements. In addition, we attempt to address concerns from the canine community regarding rare or private mutations, genetic screening using array-based technologies, non-peer reviewed tests that are being offered, and the clinical validity of certain mutations in particular breeds. Through coordination, conversation and hard work, the canine genetic testing community can strive to organize to improve testing and to provide more transparency to consumers and better outcomes for dogs. Electronic supplementary material The online version of this article (10.1007/s00439-019-02013-9) contains supplementary material, which is available to authorized users.

Several barriers present challenges to implementing pharmacogenomics into practice. This review will provide an overview of the current pharmacogenomics practices and research in Thailand, address the challenges and lessons learned from delivering clinical pharmacogenomic services in Thailand, emphasize the pharmacogenomics implementation issues that must be overcome, and identify current pharmacogenomic initiatives and plans to facilitate clinical implementation of pharmacogenomics in Thailand. Ever since the pharmacogenomics research began in 2004 in Thailand, a multitude of pharmacogenomics variants associated with drug responses have been identified in the Thai population, such as HLA-B∗15:02 for carbamazepine and oxcarbazepine, HLA-B∗58:01 for allopurinol, HLA-B∗13:01 for dapsone and cotrimoxazole, CYP2B6 variants for efavirenz, CYP2C9∗3 for phenytoin and warfarin, CYP3A5∗3 for tacrolimus, and UGT1A1∗6 and UGT1A1∗28 for irinotecan, etc. The future of pharmacogenomics guided therapy in clinical settings across Thailand appears promising because of the availability of evidence of clinical validity of the pharmacogenomics testing and support for reimbursement of pharmacogenomics testing.

Background Liquid biopsy tests capable of tumor profiling with NGS have recently received FDA approval for companion diagnostic treatment selection and tumor profiling, demonstrating the clinical validity of the identification of druggable variants with such information. As the amount of cfDNA per volume of plasma varies greatly from patient to patient, and whole blood/plasma volumes from advanced cancer patients are often limited, it would be advantageous for a liquid biopsy to be able to operate with minimal input, providing robust results across a broad spectrum of blood sample volumes and resultant cfDNA input. In this study, we evaluate the performance of Guardant360 CDx with as little as 3 mL whole blood and 5 ng cfDNA input. Methods The primary concern with low input like 3 mL whole blood is excess preservative in a blood collection tube (BCT) relative to whole blood. In a simulated short draw experiment, the same advanced cancer patient provided whole blood in BCTs with standard, elevated (2X), and high (3.3X) preservatives. We evaluated the molecule coverage across the panel at key exons and positions of interest, across genes evaluated for copy number amplifications, and at frequent fusion gene breakpoint positions. Precision and limit of detection (LoD) have been demonstrated at 5 ng input (P200010B) the lowest allowable input. For clinical utility of a liquid biopsy with low cfDNA input, we also assessed the cfDNA input of 87,305 samples tested with Guardant360 CDx or LDT from a single 10mL BCT. Results and Discussion Differences in molecule coverage between the high preservative and standard preservative were found to fall within expected technical variation (the median of log10 differences in exon-level DNA molecule coverage between short draw and reference conditions fell within +/- 0.125), indicating no meaningful loss of sensitivity for detecting somatic variants. Among the 87,305 clinical samples tested by Guardant360 CDx or LDT, median cfDNA yield was 25ng, with 98.5% yielding at least 5 ng, 88.4% at least 10ng, 73.5% at least 15 ng, and 17.9% at least 60ng. Clinically actionable biomarkers are detectable in low input samples. Of the Guardant360 CDx samples yielding 5-15ng cfDNA input, an average of 0.64 clinically significant variants was reported per sample. With the robust analytical performance demonstrated at low inputs, Guardant360 CDx (a 5ng cutoff) may provide tumor profiling results to guide therapy decisions for about 34% more patients compared to some liquid biopsies that use 2 BCTs for minimal 30ng cfDNA yield (a 15 ng cutoff). Retrospective studies for pharma research are often performed with as little as 2mL of plasma, meaning Guardant360 CDx can return results on 88.4% of such samples whereas other technologies may only be able to address 17.9% (extrapolated from the cfDNA yield distribution for 10mL whole blood yielding 4mL plasma). Citation Format: Aaron O. Richardson, Aaron Hardin, Soni Shukla, Jing Zhao, Catalin Barbacioru, Hilda Beas, Carin Espenschied, Adrian Bubie, Jamie Hutchins, Han-Yu Chuang, Tingting Jiang, Darya Chudova. The liquid biopsy Guardant360 CDx has robust performance at low inputs allowing for high rate of returning patient results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 572.

e15037 Background: Despite advances in biomarker-directed cancer therapies to predict tumor response to treatment, precision oncology remains an imprecise science. Tumor organoid drug screens present an opportunity to test multiple potentially effective therapies simultaneously before exposing a patient to treatment toxicities. Preliminary studies have established the analytic validity; however, the clinical validity of the tumor organoid response to a drug to predict the tumor response in patients is unclear. Methods: In order to establish the clinical validity of an organoid drug screen, a clinical disease model should have the following features to enable comparison of the tumor’s clinical response to treatment and the organoid’s response to the same treatment. First, a fresh tissue biopsy (non-bone) needs to be obtained for organoid development prior to the start of systemic treatment. Priority should be given to tumors known to successfully grow organoids. Disease models where the standard of care systemic treatment is a single cytotoxic or targeted agent would best assess correlation between the drug screen and patient response, such as metastatic breast, cervical, or prostate cancer. This would often lead to enrolling patients on later line systemic therapies. Studies should avoid drugs whose mechanism of action leverages the patient metabolism or tumor microenvironment (e.g. immunotherapy, aromatase inhibitors, VEGF inhibitors). Patient should have measurable disease that can be measured clinically, radiographically, or pathologically and using standardized response evaluation criteria (e.g. RECIST). Next generation sequencing would assess genomic concordance between the tumor in the patient and organoid. These studies would determine the feasibility and timeliness of prospectively developing tumor organoids that is sufficient to perform a drug screen. Results: We propose two research models to evaluate the clinical validity of tumor organoid drug screens: a metastatic solid tumor and neoadjuvant solid tumor disease model. Metastatic disease models provide an opportunity to assess response across multiple cancer types at the time of progression and initiation of next line of therapy. The efficacy of chemotherapy can be determined using objective data from radiologic response (RECIST). In neoadjuvant models, pathologic (pCR) and radiologic response can provide objective data for organoid response. These study design features will lay the framework for determining the clinical utility of organoid drug screens. Conclusions: We call for clinical studies assessing the clinical validity of tumor organoid drug screens and determining their concordance with patient response to systemic therapy. Advancements in clinically validated tumor organoids have the potential to fundamentally shift clinical paradigms and improve patient outcomes in cancer treatment.

Background/AimTo investigate the clinical validity of the Guided Progression Analysis definition (GPAD) and cluster-based definition (CBD) with the Humphrey Field Analyzer 10-2 test in diagnosing glaucomatous visual field (VF) progression, and to introduce a novel definition with optimised specificity by combining the ‘any-location’ and ‘cluster-based’ approaches (hybrid definition).Methods64 400 stable glaucomatous VFs were simulated from 664 pairs of 10-2 tests (10 sets × 10 VF series × 664 eyes; data set 1). Using these simulated VFs, the specificity to detect progression and the effects of changing the parameters (number of test locations or consecutive VF tests, and percentile cut-off values) were investigated. The hybrid definition was designed as the combination where the specificity was closest to 95.0%. Subsequently, another 5000 actual glaucomatous 10-2 tests from 500 eyes (10 VFs each) were collected (data set 2), and their accuracy (sensitivity, specificity and false positive rate) and the time needed to detect VF progression were evaluated.ResultsThe specificity values calculated using data set 1 with GPAD and CBD were 99.6% and 99.8%. Using data set 2, the hybrid definition had a higher sensitivity than GPAD and CBD, without detriment to the specificity or false positive rate. The hybrid definition also detected progression significantly earlier than GPAD and CBD (at 3.1 years vs 4.2 years and 4.1 years, respectively).ConclusionsGPAD and CBD had specificities of 99.6% and 99.8%, respectively. A novel hybrid definition (with a specificity of 95.5%) had higher sensitivity and enabled earlier detection of progression.

Ascertaining a diagnosis through exome sequencing can provide potential benefits to patients, insurance companies, and the healthcare system. Yet, as diagnostic sequencing is increasingly employed, vast amounts of human genetic data are produced that need careful curation. We discuss methods for accurately assessing the clinical validity of gene–disease relationships to interpret new research findings in a clinical context and increase the diagnostic rate. The specifics of a gene–disease scoring system adapted for use in a clinical laboratory are described. In turn, clinical validity scoring of gene–disease relationships can inform exome reporting for the identification of new or the upgrade of previous, clinically relevant gene findings. Our retrospective analysis of all reclassification reports from the first 4 years of diagnostic exome sequencing showed that 78% were due to new gene–disease discoveries published in the literature. Among all exome positive/likely positive findings in characterized genes, 32% were in genetic etiologies that were discovered after 2010. Our data underscore the importance and benefits of active and up‐to‐date curation of a gene–disease database combined with critical clinical validity scoring and proactive reanalysis in the clinical genomics era.

We present the results of the clinical validity in the screening of idiopathic scoliosis with a nonharming method of back surface topography by means of structured light projection. A total of 155 patients were evaluated (mean age 13.3 years). They were divided into two groups: pathologic patients (scoliosis) and nonpathologic patients (control and asymmetries). An analytical case-control study was carried out. Our topographic method obtained 92% sensitivity and 74% specificity as a screening test in identifying patients with scoliosis (P=0.05). We could quantify the vertebral deformity of scoliosis in the three spatial planes by means of three topographic variables, Horizontal Plane Deformity Index, Posterior Trunk Symmetry Index and Columnar Profile, and to elaborate a combined screening algorithm with good reliability parameters.

OBJECTIVE To determine the clinical and construct validity of the nursing diagnosis “decreased cardiac output” (DCO) in patients with chronic heart failure. METHODS Cross-sectional study. RESULTS A total of 200 people were studied. The defining characteristics with the highest prevalence were as follows: arrhythmia (62.5%) and fatigue (61.5%). Adjustment measures such as infit and outfit were maintained between 0.50 and 1.56 and the total variance explained by the measures was 29.3%. CONCLUSIONS This study determined the clinical validity of the nursing diagnosis DCO. Regarding construct validity, adjustment of the defining characteristics to the Rasch model was observed. IMPLICATIONS FOR NURSING PRACTICE This study improves the evidence-based practice of nursing and strengthened the role of the nurse who leads care to this population. OBJETIVO Determinar la validez clinica y de constructo del diagnostico de enfermeria “Disminucion del Gasto Cardiaco” en pacientes con falla cardiaca cronica. METODOS Estudio de corte transversal. RESULTADOS Un total de 200 pacientes fueron estudiados. Las caracteristicas definitorias con las mayores prevalencias fueron: arritmia (62.5%) y fatiga (61.5%). Medidas de ajuste como el infit y outfit se mantuvieron entre 0.50 y 1.56. El total de la varianza explicada por las medidas fue de 29.3%. CONCLUSIONES Este estudio determino la validez clinica del diagnostico de enfermeria “Disminucion del Gasto Cardiaco”. En cuanto a la validez de constructo, se observo que 19 de las 21 caracteristicas definitorias se ajustaron al modelo Rasch. IMPLICACIONES PARA LA PRACTICA DE ENFERMERIA Este estudio mejora la practica basada en la evidencia de enfermeria y fortalece el rol de las enfermeras que lideran el cuidado en esta poblacion.

Parenting behaviours play a major role in the evolution of infant sleep. Sleep problems in infancy have been associated with excessive parental involvement at night-time, and with shorter delays in response to infant night wakings and signalling. Infant crying and sleep problems are linked, yet little is known about the impact of parental responses to crying on infant sleep patterns. This study examined the hypothesis that lower parental tolerance for crying is associated with infant sleep problems. We studied 144 married couples divided into three groups: parents of infants suffering from night-waking problems (i.e. the clinical group), parents of infants without sleep problems and childless couples. Crying tolerance was assessed using questionnaires, audio recordings of crying infants and using a novel paradigm, in which participants were shown a video of a crying infant and asked when they would intervene. Parents in the clinical group demonstrated shorter intervention delays in the crying infant clip (group effect: P

Purpose Medical society guidelines recommend offering genotyping-based cystic fibrosis (CF) carrier screening to pregnant women or women considering pregnancy. We assessed the performance of sequencing-based CF screening relative to genotyping, in terms of analytical validity, clinical validity, clinical impact, and clinical utility. Methods Analytical validity was assessed using orthogonal confirmation and reference samples. Clinical validity was evaluated using the CFTR2 database. Clinical impact was assessed using ~100,000 screened patients. Three screening strategies were compared: genotyping 23 guideline-recommended variants (“CF23”), sequencing all coding bases in CFTR (“NGS”), and sequencing with large copy-number variant (CNV) identification (“NGS + CNV”). Clinical utility was determined via self-reported actions of at-risk couples (ARCs). Results Analytical accuracy of NGS + CNV was 100% for SNVs, indels, and CNVs; interpretive clinical specificity relative to CFTR2 was 99.5%. NGS + CNV detected 58 ARCs, 18 of whom would have gone undetected with CF23 alone. Most ARCs (89% screened preconceptionally, 56% prenatally) altered pregnancy management, and no significant differences were observed between ARCs with or without at least one non-CF23 variant. Conclusion Modern NGS and variant interpretation enable accurate sequencing-based CF screening. Limiting screening to 23 variants does not improve analytical validity, clinical validity, or clinical utility, but does fail to detect approximately 30% (18/58) of ARCs.

Total elbow replacement (TER) is a clinically successful procedure yet isolated, gross mechanical complications associated with implant durability persist. The objectives of this study were to (1) develop a clinically relevant in vitro methodology to replicate the reported damage modes and (2) demonstrate durability improvements of a next-generation linked, semiconstrained design. Two TER prostheses were tested on a biaxial test frame at 1.4 Hz in 37 ± 3° deionized water through 0° to 130° flexion/extension at various load levels simulating high demand, posttraumatic patients until either component failure or run out to 200 000 cycles. The damage patterns of tested components were qualitatively compared to retrieved components to establish the clinical validity of the methodology. The run out load of design 1 was equivalent to 100 N weight in hand (WIH). Specimens tested at higher load levels exhibited multimodal damage consistent in appearance with the clinical literature. The minimum run out load of design 2 was 110 N WIH with no significant damage observed on the components. The methodology developed here was shown to reproduce the clinical damage modes associated with TER in high demand, posttraumatic patients. The method was able to distinguish performance differences within and between 2 different linked, semiconstrained designs.

Objective To assess the learnability of two magnetic resonance imaging (MRI) grading systems for lumbar central canal stenosis based on inter-observer agreement and test-retest reliability of doctors with no prior knowledge of the two systems. Materials and methods Two clinical fellows, one novice radiology resident, one neurosurgeon, and one orthopedic surgeon, who were unaware of the two qualitative MRI grading systems prior to this study, acquainted themselves with the teaching files. All five observers independently assessed the LCCS grade of 70 patients using T2-weighted axial magnetic resonance images at the L2-3, L3-4, L3-4, and L5-S1 disc levels. Analysis was performed twice at an interval of two months. Results The inter-observer agreement among all five readers was excellent and test-retest reliability was moderate to excellent for both the Schizas and Lee systems. Positive percentage agreements were found to be over 0.8 in almost all observers with relatively narrow 95% confidence limits. Conclusion Both Schizas and Lee MRI grading systems for LCCS are reliable grading systems, and can be used as a learnable method for both clinicians and radiologists.

PurposeProper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene-disease relationships. The Clinical Genome Resource (ClinGen) has developed a semi-quantitative framework to assign clinical validity to gene-disease relationships.MethodsThe ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene-disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss.ResultsThe final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website (https://search.clinicalgenome.org/kb/gene-validity).ConclusionThis gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.

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.

Objective: To investigate the validity of microscopy as a diagnostic tool for urinary tract infection in general practice. Methods: (Design/setting) A systematic review was conducted by searching Medline for clinical studies made in general practice, outpatient clinics or similar settings in which the accuracy/validity of microscopy was evaluated with urine culture as the reference standard. Results: Our search resulted in 108 titles. 28 potentially eligible studies were retrieved for full-text reading. We included eight studies involving 4582 patients in this review. The quality of the studies was moderate to high. Specificity ranged from 27% to 100%, sensitivity from 47% to 97%. The variation between studies did not allow for meta-analysis. Conclusion: We did not find substantial evidence to determine the clinical validity of microscopy performed in general practice on urine samples from patients with symptoms of UTI.Key pointsUrinary tract infection is common in general practice. Methods for precise diagnosis are needed in order to avoid inappropriate treatment. Currently no evidence-based consensus exists regarding the use of urinary microscopy in general practice.We did not find substantial evidence to determine the overall clinical validity of microscopy performed in general practice on urine samples from patients with symptoms of UTI.Light microscopy with oil immersion had high sensitivity and specificity but is time-consuming. Phase-contrast microscopy is quick and had high specificity but lower sensitivity.

To provide an overview of the selection process and annual updates of the child mental health measures within the Child Core Set, describe national and statewide adherence rates, and summarize findings from a systematic literature review examining measure adherence rates and whether adherence is associated with improved clinical outcomes. Five national quality measures target child mental health care processes. On average, national adherence varied widely by state, and performance did not substantially improve during the past 5 years. Mean national adherence rates for the two measures related to timeliness of care were below 50%. For each measure, scientific evidence to support the association between adherence and improved clinical outcomes was scarce. Investment in academic-agency partnered research to standardize methods for publicly reporting adherence to national child mental health quality measures and validation of these measures should be a national priority for child healthcare research.

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.

Although pharmacogenomics has the potential to personalize drug therapy, economic evaluations showing clinical benefits and cost-effectiveness would go a long way to facilitate implementation. Testing of single genes has shown some benefits as well as limitations, and some investigators advocated the use of combinatorial pharmacogenomics approach. In addition, debates continue regarding the most appropriate way of evaluating cost–benefits. Review of alternative approaches to assessing clinical validity and utility, as well as cost-effectiveness of pharmacogenomics testing within the psychiatric discipline, show some promises and progress, as well as questions to be addressed, for these two important aspects of pharmacogenomics testing.

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.

Although circulating tumor cells (CTCs) are rare, they have been frequently investigated as diagnostic, prognostic, and predictive biomarkers in numerous entities of solid tumors (i.e., in breast, lung, prostate, and colorectal cancers). CTCs have been studied most extensively in breast cancer (BC), with level-of-evidence-1 studies supporting the clinical validity of CTC enumeration in both early and metastatic diseases. However, these tumor cells are not yet used in clinical practice because their clinical utility has not been demonstrated. This chapter presents an overview of the current clinical validity and utility of CTCs in metastatic and nonmetastatic BC. Furthermore, an overview of the developments of ongoing research studies on CTCs is presented.

Recent studies have led to considerable advances in the identification of genetic variants associated with type 1 and type 2 diabetes. An approach for converting genetic data into a predictive measure of disease susceptibility is to add the risk effects of loci into a polygenic risk score. In order to summarize the recent findings, we conducted a systematic review of studies comparing the accuracy of polygenic risk scores developed during the last two decades. We selected 15 risk scores from three databases (Scopus, Web of Science and PubMed) enrolled in this systematic review. We identified three polygenic risk scores that discriminate between type 1 diabetes patients and healthy people, one that discriminate between type 1 and type 2 diabetes, two that discriminate between type 1 and monogenic diabetes and nine polygenic risk scores that discriminate between type 2 diabetes patients and healthy people. Prediction accuracy of polygenic risk scores was assessed by comparing the area under the curve. The actual benefits, potential obstacles and possible solutions for the implementation of polygenic risk scores in clinical practice were also discussed. Develop strategies to establish the clinical validity of polygenic risk scores by creating a framework for the interpretation of findings and their translation into actual evidence, are the way to demonstrate their utility in medical practice.

Cardiopulmonary exercise testing (CPET) quantifies total exercise performance by assessing peak exercise parameters, however peak exercise may not always be achieved. Clinical validity of submaximal exercise parameters may be helpful to assess cardiac reserve in children. Retrospectively reviewed

Cancer, a local disease at an early stage, systemically evolves as it progresses by triggering alterations in surrounding microenvironment, disturbing immune surveillance and further disseminating its molecular contents into circulation. This pathogenic characteristic of cancer makes the use of biofluids such as blood/serum/plasma, urine, tear and cerebrospinal fluids credible surrogates harboring tumor tissue-derived molecular alterations for the detection of cancer. Most importantly, a number of recent reports have credentialed the clinical validity of saliva for the detection of systemic diseases including cancers. In this review, we discussed the validity of saliva as credible biofluid and clinical sample type for the detection of cancers. We have presented the molecular constituents of saliva that could mirror the systemic status of our body and recent findings of salivaomics associated with cancers. Recently, liquid biopsy to detect cancer-derived circulating tumor DNA has emerged as a credible cancer-detection tool with potential benefits in screening, diagnosis and also risk management of cancers. We have further presented the clinical validity of saliva for liquid biopsy of cancers and a new technology platform based on electrochemical detection of cancer-derived ctDNA in saliva with superior sensitivity and point-of-care potential. The clinical utilities of saliva for the detection of cancers have been evidenced, but biological underpinning on the existence of molecular signatures of cancer- origin in saliva, such as via exosomal distribution, should be addressed in detail.

BACKGROUND While higher genetic risk score (GRS) has been statistically associated with increased disease risk (broad-sense validity), the concept and tools for assessing the validity of reported GRS values from tests (narrow-sense validity) are underdeveloped. METHODS We propose two benchmarks for assessing the narrow-sense validity of GRS. The baseline benchmark requires that the mean GRS value in a general population approximates 1.0. The calibration benchmark assesses the agreement between observed risks and estimated risks (GRS values). We assessed benchmark performance for three prostate cancer (PCa) GRS tests, derived from three SNP panels with increasing stringency of selection criteria, in a PCa chemoprevention trial where 714 of 3225 men were diagnosed with PCa during the 4-year follow-up. RESULTS GRS from Panels 1, 2, and 3 were all statistically associated with PCa risk; P = 5.58 × 10-3 , P = 1 × 10-3 , and P = 1.5 × 10-13 , respectively (broad-sense validity). For narrow-sense validity, the mean GRS value among men without PCa was 1.33, 1.09, and 0.98 for Panels 1, 2, and 3, respectively (baseline benchmark). For assessing the calibration benchmark, observed risks were calculated for seven groups of men with GRS values

Aim: To evaluate factors influencing cardiologists’ perspectives about pharmacogenomic (PGx) testing in clinical practice. Patients & methods: Semistructured interviews with practicing cardiologists were qualitatively analyzed to identify common themes. Results: Five themes were identified among 16 cardiologists from four specialties (n = 5 general cardiology, n = 3 electrophysiology, n = 2 adult congenital and n = 6 heart failure/transplant): cardiologists’ knowledge and needs, perceived clinical validity and utility of PGx testing, dissemination and management of PGx results, patient-related considerations and incidental findings. Conclusion: Lack of evidence was considered by many cardiologists to be a major barrier hindering the use of PGx testing. However, they would consider adopting PGx if they were provided additional education, ongoing support and evidence supporting the clinical utility of PGx testing in cardiovascular medicine.

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.

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 re-evaluating curated gene-disease associations will need to be determined. To provide guidance on how often a gene-disease association should be re-curated, 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 re-classification 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 re-curate a gene-disease association.

Circulating tumor cells (CTCs) are particularly rare in non-metastatic breast cancer, and the clinical validity of CTC detection in that clinical setting was initially not well recognized. A cytological CTC detection device (CellSearch) fulfilling the CLIA requirements for analytical validity was subsequently developed and, in 2008, we reported the first study (REMAGUS02) showing that distant metastasis-free survival was shorter in early breast cancer patients with one or more CTCs. In the past 10 years, other clinical studies and meta-analyses have established CTC detection as a level-of-evidence 1 prognostic biomarker for local relapses, distant relapses, and overall survival. This review summarizes available data on CTC detection and the promises of this proliferation- and subtype-independent metastasis-associated biomarker in early breast cancer patients.

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. Keywords:Alzheimer's disease; Amyloid-PET; Clinical validity; Cost-effectiveness; Mild cognitive impairment; Subjective cognitive decline.