Guidelines For Interpretation Research Articles

Measuring Clinically Meaningful Change in Outcomes for Youth With Chronic Pain Following Graded Exposure Treatment.

Functional improvement is a critical outcome for individuals living with chronic pain. Graded exposure treatment (GET) has been associated with statistically significant improvements in functional outcomes for youth with chronic pain by targeting pain-related fear and avoidance. The aim of the present study was to explore clinically meaningful change in outcomes in adolescents with chronic pain following participation in a GET, and to then classify patients as treatment responders versus nonresponders. Participants included 27 youth (Mage=13.5) with chronic pain enrolled in a recently published single-arm randomized baseline trial of GET Living. Reliable change at the individual level was assessed using the Reliable Change Index (RCI). Adolescents were classified as treatment responders if they achieved a reliable change in outcomes across time points and also demonstrated a change in clinical severity range in the expected direction (ie, from severe to moderate). Reliable and clinically significant improvements in pain-related fear and avoidance, functional disability, and school functioning were demonstrated at discharge, with improvements maintained at 3-month and 6-month follow-up. Among core outcomes, 48% (n=13) of patients were classified as treatment responders in one or more outcomes at discharge, with this increasing to 76% (n=19) at 3-month follow-up. Examining reliable and clinically meaningful change (vs. statistical significance alone) provides a way to examine treatment response to an intervention and to enhance the interpretability of findings, helping to bridge the gap between clinical trials and clinical practice by providing guidelines for interpretation.

Culture and the Court Interpreter

In New Zealand, interpreters provide ‘vital services for nearly 10,000 hearings a year in more than 150 languages’ (Ministry of Justice chief operating officer, Carl Crafer according to Nichols, 2021). Despite this, the Ministry of Justice Guidelines for Interpreters (Ministry of Justice, 2021) (‘MOJ Guidelines’) provide very limited guidance on how court interpreters are expected to approach issues related to potential intercultural miscommunication. In this paper, I use the phrase ‘potential intercultural miscommunication’ to mean the possibility of otherwise unrecognised interpersonal misunderstandings occurring, due to differing customs, norms, and behaviours. This paper aims to examine the potential for such undetected intercultural miscommunications to occur in the criminal court, the impact they can have and what obligations, if any, should be placed on court interpreters and judges when such issues arise.

EP374: Variant classification changes over time at a clinical molecular diagnostic laboratory

As genetic testing increasingly informs clinical decision making across medical specialties, accurate variant interpretation is essential to ensure patients receive appropriate care. Current guidelines for genomic sequence variant interpretation delineate the evidence that should be incorporated in variant assessments as well as how different types of evidence should be weighted. Variants can be re-interpreted and reclassified over time as new evidence accrues. The Advanced Molecular Diagnostics Laboratory (AMDL) at Mount Sinai Hospital in Toronto, Ontario, provides publicly funded multigene panel testing for patients with suspected hereditary disorders.

OP034: Evaluation of the 2019 ACMG-ClinGen guidelines for interpretation of copy-number variants with borderline classifications at an academic clinical diagnostics laboratory

Copy-number variation is a source of both genetic diversity and Mendelian disease. Analysis of copy-number variants (CNVs) is an essential and frequently utilized component of medical genetics for a wide variety of patient indications. In 2019, the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) developed new technical standards for the interpretation of CNVs, introducing a semi-quantitative classification system that aims to foster greater standardization and consistency of classifications between laboratories.

Umbilical Cord Entanglement.

Umbilical Cord Entanglement.

A phenotype-enhanced variant classification framework to decrease the burden of missense variants of uncertain significance in type 1 long QT syndrome.

Pathogenic/likely pathogenic (P/LP) variants in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). Despite the revamped 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNQ1 variants of uncertain significance (VUS) in patients with LQTS remains ∼30%. The purpose of this study was to determine whether a phenotype-enhanced (PE) variant classification approach could reduce the VUS burden in LQTS genetic testing. Retrospective analysis was performed on 79 KCNQ1 missense variants in 356 patients from Mayo Clinic and an independent cohort of 42 variants in 225 patients from Amsterdam University Medical Center (UMC). Each variant was classified initially using the ACMG guidelines and then readjudicated using a PE-ACMG framework that incorporated the LQTS clinical diagnostic Schwartz score plus 4 "LQT1-defining features": broad-based/slow upstroke T waves, syncope/seizure during exertion, swimming-associated events, and a maladaptive LQT1 treadmill stress test. According to the ACMG guidelines, Mayo Clinic variants were classified as follows: 17 of 79 P variants (22%), 34 of 79 LP variants (43%), and 28 of 79 VUS (35%). Similarly, for Amsterdam UMC, the variant distribution was 9 of 42 P variants (22%), 14 of 42 LP variants (33%), and 19 of 42 variants VUS (45%). After PE-ACMG readjudication, the total VUS burden decreased significantly from 28 (35%) to 13 (16%) (P = .0007) for Mayo Clinic and from 19 (45%) to 12 (29%) (P = .02) for Amsterdam UMC. Phenotype-guided variant adjudication decreased significantly the VUS burden of LQT1 case-derived KCNQ1 missense variants in 2 independent cohorts. This study demonstrates the value of incorporating LQT1-specific phenotype/clinical data to aid in the interpretation of KCNQ1 missense variants identified during genetic testing for LQTS.

EP354: A systematic approach for applying disease-specific phenotype in clinical variant interpretation

The 2015 ACMG/AMP clinical variant interpretation guidelines incorporate an individual’s phenotype, including presenting features and family history consistent with a particular genetic cause of disease, across multiple pathogenicity criteria. However, they do not give detailed guidance on how to define or weight such disease-specific features, leading to uncertainty and discordant use in clinical variant interpretation. Here, we assessed the recommendations of existing ClinGen Variant Curation Expert Panels (VCEPs) for applying phenotypic data for their associated gene-disease pairs, and used this to create a broader framework to support more systematic use of phenotypic features in clinical variant interpretation.

EP404: Evidence supporting the pathogenicity of the NADSYN1 c.1717G>A (p.Ala573Thr) variant in individuals referred for clinical testing

Vertebral, cardiac, renal, and limb defects syndrome 3 (VCRL3; OMIM #618845) is an autosomal recessive multiple congenital anomaly syndrome caused by pathogenic variants in the NADSYN1 gene. NADSYN1 encodes a nicotinamide adenine dinucleotide (NAD) synthetase that is part of the de novo NAD synthesis pathway. Other genes involved in this pathway include HAAO and KYNU. Genetic variants in any of these genes result in reduced de novo NAD synthesis and cause congenital anomalies of the heart, kidney, and vertebrae. Of note, presence of these three features is also considered clinical evidence for vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities (VACTERL) association, which is often a diagnosis of exclusion (ie, other genetic conditions with overlapping features must be ruled out before assigning this diagnosis). The recommended approach for genetic testing in possible VACTERL patients is to either pursue a comprehensive testing option, such as exome or genome sequencing, or a panel approach with the most likely candidates. The NADSYN1 gene is included on a VACTERL Association and Related Disorders panel and several patients were noted to be homozygous for the NADSYN1 c.1717G>A (p.Ala573Thr) variant, thus providing additional evidence for both the pathogenicity and high carrier frequency of this change. To date, we have identified five patients who are homozygous for the NADSYN1 (NM_018161.4) c.1717G>A (p.Ala573Thr) variant. One patient was identified through targeted testing, one through testing with the VACTERL Association and Related Disorders panel, and three through exome sequencing. The first four cases were from pregnancies evaluated for the differential diagnosis of VACTERL association via panel testing or exome sequencing. All four fetuses were reported to have cardiac malformation and segmental vertebral anomalies. Parental data was available for three of the four fetuses, and all parents tested were heterozygous for the NADSYN1 c.1717G>A (p.Ala573Thr) variant. All cases denied consanguinity. In contrast to the severe and early onset features of the other four patients identified, the targeted testing case was an adult patient who previously had the NADSYN1 c.1717G>A variant identified in a research study. This individual was noted to have cardiac defects, vertebral defects, and short stature. This variant is relatively common in non-Finnish Europeans with an allele frequency of 0.15% in the gnomAD v2 dataset. Five patients from four families with VCRL3 have been described in the literature. Of these patients, three had the c.1717G>A variant: two homozygous siblings and one compound heterozygote with a loss of function variant on the opposite allele. Parental sequencing data confirmed the biallelic variants in all reported patients. In addition, yeast model functional studies performed by Szot and colleagues demonstrated that the p.Ala573Thr change diminished NAD synthetase activity and reduced yeast viability, consistent with a loss of function mechanism. Taken together, although the NADSYN1 c.1717G>A (p.Ala573Thr) has a relatively high minor allele frequency, there is sufficient evidence for this variant to be classified as pathogenic using ACMG/AMP variant classifications and internal variant interpretation guidelines. The NADSYN1 c.1717G>A (p.Ala573Thr) variant should be interpreted as pathogenic given the 5 additional homozygous patients and parental segregation data presented here. Additionally, the diagnosis of VCRL3 in an adult patient suggests that although penetrance for NAD deficiency is complete, variable expressivity is observed and could be explained by other genetic or non-genetic factors modulating disease severity. Given the high population frequency of this variant, genetic testing for VACTERL association should always include evaluation of NADSYN1 to consider VCRL3 in the differential diagnosis.

EP421: Development of an in-house whole transcriptome test for evaluation of splicing VUS variants: Experience and challenges in variant interpretation

Variants with potential splicing impact are often deemed uncertain clinical significance (VUS) due to the lack of functional evidence. Previous studies for these variants by targeted RNAseq panels were limited by the logistics of acquiring additional blood sample for RNA collection after they were identified by initial DNA tests. Moreover, detailed guidelines for interpreting complex RNAseq results were lacking, especially in the setting of multiple naturally occurring isoforms. To address this, we have developed a whole transcriptome (RNAseq) test aiming to facilitate reclassification of VUS splicing variants identified from Clinical Exome and Genome Sequencing tests, by providing simplified sample submission process, as well as comprehensive and detailed clinical interpretation guideline of the RNAseq result.

An Examination of the Sex-Specific Nature of Nutrition Assessment within the Nutrition Care Process: Considerations for Nutrition and Dietetics Practitioners Working with Transgender and Gender Diverse Clients

An Examination of the Sex-Specific Nature of Nutrition Assessment within the Nutrition Care Process: Considerations for Nutrition and Dietetics Practitioners Working with Transgender and Gender Diverse Clients

User experiences of digital prostheses in daily functioning in people with an amputation of thumb or finger

Study Design"Qualitative research design using interpretative phenomenological analysis (IPA) to interpret users’ experiences with digital prostheses. BackgroundDigital prostheses are rarely used, and little is known about the experiences of traumatic finger amputees with digital prostheses. When advising patients regarding digital prostheses, it is crucial for professionals to understand users experiences of wearing a digital prosthesis and the meaning attached to wearing a digital prosthesis. Purpose of studyThe aim of this study was to explore and understand users experiences of wearing a digital prostheses in daily functioning. MethodsIndividual semi-structured interviews were conducted, recorded, and transcribed. The written interview texts were analysed following Interpretative phenomenological analysis guidelines. ResultsFour participants were interviewed. They experienced the prostheses as valuable additions to their daily functioning. Three different themes relating to wearing and using digital prostheses emerged from in-depth analysis of the data: How the prosthesis supporting them regaining a ‘grip’ on life, reduced overload on unaffected side and restored body image. ConclusionsThis study provides a deeper understanding of the experiences of people with digital amputations who use prostheses. Most importantly, that a prosthesis is of crucial importance for participants to be able to act independently and autonomously as well as to participate in family, work and social environments. This insight will help practitioners when considering, with clients the most appropriate digital prosthesis to meet their goals.

A bibliometric analysis of the cause of sudden unexplained death in forensic medicine: Research trends, hot spots and prospects

To better understand the cause of sudden unexplained death, our group evaluated the scientific results of related studies in a global context. A systematic search of the Web of Science, PubMed and MEDLINE databases identified 2001 studies related to this field published from 1997 to 2020. The studies were analyzed using bibliometric methods, and statistical maps were drawn to explore research trends and research frontiers. Sudden cardiac death and sudden unexpected epilepsy death were the two major causes of sudden unexplained deaths. With the rapid development of high-throughput sequencing technology and bioinformatics in the past 10 years, molecular autopsy has become an effective research method as well as a research hotspot for exploring the cause of sudden unexplained deaths. However, molecular autopsy is underutilized in the investigation of sudden unexpected death in epilepsy. Developing standardized guidelines for diagnostic strategies for the deceased and their families, expanding the screening of mutation spectrum of related diseases, studying the association between variants and diseases in complex genetic diseases, and improving variants interpretation guidelines and disease sequencing databases are future research directions.

A machine learning approach based on ACMG/AMP guidelines for genomic variant classification and prioritization

Genomic variant interpretation is a critical step of the diagnostic procedure, often supported by the application of tools that may predict the damaging impact of each variant or provide a guidelines-based classification. We propose the application of Machine Learning methodologies, in particular Penalized Logistic Regression, to support variant classification and prioritization. Our approach combines ACMG/AMP guidelines for germline variant interpretation as well as variant annotation features and provides a probabilistic score of pathogenicity, thus supporting the prioritization and classification of variants that would be interpreted as uncertain by the ACMG/AMP guidelines. We compared different approaches in terms of variant prioritization and classification on different datasets, showing that our data-driven approach is able to solve more variant of uncertain significance (VUS) cases in comparison with guidelines-based approaches and in silico prediction tools.

An Unexpected Cause of Recurrent Fetal Decelerations

An Unexpected Cause of Recurrent Fetal Decelerations

Isokinetic hamstring and quadriceps strength interpretation guideline for football (soccer) players with ACL reconstruction: a Delphi consensus study in the Netherlands

ABSTRACT Strength testing is a key part of rehabilitation and return to sport (RTS) decision making for football players after anterior cruciate ligament reconstruction (ACLR). Isokinetic testing has been the gold standard for strength measurement for decades, but a uniform protocol and clinical implications of test results are lacking. Therefore, this study aimed to 1) develop a uniform protocol for football players based on knowledge and experience from experts in the field of ACL rehabilitation and 2) clarify the clinical interpretation of different isokinetic test outcomes. In a structured Delphi consensus procedure 42 experts (98% full response rate) fulfilled three rounds that involved a survey, content analysis and anonymised feedback report for each round. Surveys addressed the isokinetic protocol, evaluation report and torque–angle curve of the isokinetic test for strength evaluation in football players after ACLR. The final protocol consisted of concentric knee flexion and extension isokinetic testing with 5 repetitions at 60°/sec, 20 repetitions at 180°/sec and 15 repetitions at 300°/sec and 60 seconds rest between sets. All parameters were deemed valuable, with Peak Torque, Max Rep Total Work, Total Work, Range of Motion and Agonist to Antagonist ratio being considered key for clinical interpretation. For qualitative assessment, it was advised to assess the shape, course, volume, potential dips, peak, and build-up to the peak of the parabola. This Delphi consensus study provided a guideline for data collection and clinical interpretation of isokinetic strength testing in football players after ACLR.

Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC)

PurposeSeveral professional societies have published guidelines for the clinical interpretation of somatic variants, which specifically address diagnostic, prognostic, and therapeutic implications. Although these guidelines for the clinical interpretation of variants include data types that may be used to determine the oncogenicity of a variant (eg, population frequency, functional, and in silico data or somatic frequency), they do not provide a direct, systematic, and comprehensive set of standards and rules to classify the oncogenicity of a somatic variant. This insufficient guidance leads to inconsistent classification of rare somatic variants in cancer, generates variability in their clinical interpretation, and, importantly, affects patient care. Therefore, it is essential to address this unmet need. MethodsClinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group and ClinGen Germline/Somatic Variant Subcommittee, the Cancer Genomics Consortium, and the Variant Interpretation for Cancer Consortium used a consensus approach to develop a standard operating procedure (SOP) for the classification of oncogenicity of somatic variants. ResultsThis comprehensive SOP has been developed to improve consistency in somatic variant classification and has been validated on 94 somatic variants in 10 common cancer-related genes. ConclusionThe comprehensive SOP is now available for classification of oncogenicity of somatic variants.

A practical guide to interpreting germline variants that drive hematopoietic malignancies, bone marrow failure, and chronic cytopenias

PurposeThe American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines for germline variant interpretation are implemented as a broad framework by standardizing variant interpretation. These rules were designed to be specified, but this process has not been performed for most of the 200 genes associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias. Because guidelines on how to perform these gene specifications are lacking, variant interpretation is less reliable and reproducible. MethodsWe have used a variety of methods such as calculations of minor allele frequencies, quasi-case–control studies to establish thresholds, proband counting, and plotting of receiver operating characteristic curves to compare different in silico prediction tools to design recommendations for variant interpretation. ResultsWe herein provide practical recommendations for the creation of thresholds for minor allele frequencies, in silico predictions, counting of probands, identification of functional domains with minimal benign variation, use of constraint Z-scores and functional evidence, prediction of nonsense-mediated decay, and assessment of phenotype specificity. ConclusionThese guidelines can be used by anyone interpreting variants associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias to develop criteria for reliable, accurate, and reproducible germline variant interpretation.

The genetic architecture of pediatric cardiomyopathy

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1× 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.

A Coordinated Sampling and Identification Methodology for Larval Parasitoids of Spotted-Wing Drosophila.

We provide recommendations for sampling and identification of introduced larval parasitoids of spotted-wing drosophila, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae). These parasitoids are either under consideration for importation (aka classical) biological control introductions, or their adventive (presumed to have been accidentally introduced) populations have recently been discovered in North America and Europe. Within the context of the ecology of D. suzukii and its parasitoids, we discuss advantages and disadvantages of estimating larval parasitism levels using different methods, including naturally collected fruit samples and sentinel baits. For most situations, we recommend repeated sampling of naturally occurring fruit rather than using sentinel baits to monitor seasonal dynamics of host plant-Drosophila-parasitoid associations. We describe how to separate Drosophilidae puparia from host fruit material in order to accurately estimate parasitism levels and establish host-parasitoid associations. We provide instructions for identification of emerging parasitoids and include a key to the common families of parasitoids of D. suzukii. We anticipate that the guidelines for methodology and interpretation of results that we provide here will form the basis for a large, multi-research team sampling effort in the coming years to characterize the biological control and nontarget impacts of accidentally and intentionally introduced larval parasitoids of D. suzukii in several regions of the world.

Minimal Residual Disease Analysis by Monitoring Immunoglobulin and T-Cell Receptor Gene Rearrangements by Quantitative PCR and Droplet Digital PCR.

Analysis of immunoglobulin and T-cell receptor gene rearrangements by real-time quantitative polymerase chain reaction (RQ-PCR) is the gold standard for sensitive and accurate minimal residual disease (MRD) monitoring; it has been extensively standardized and guidelines have been developed within the EuroMRD consortium ( www.euromrd.org ). However, new generations of PCR-based methods are standing out as potential alternatives to RQ-PCR, such as digital PCR technology (dPCR), the third-generation implementation of conventional PCR, which has the potential to overcome some of the limitations of RQ-PCR such as allowing the absolute quantification of nucleic acid targets without the need for a calibration curve. During the last years, droplet digital PCR (ddPCR) technology has been compared to RQ-PCR in several hematologic malignancies showing its proficiency for MRD analysis. So far, no established guidelines for ddPCR MRD analysis and data interpretation have been defined and its potential is still under investigation. However, a major standardization effort is underway within the EuroMRD consortium ( www.euromrd.org ) for future application of ddPCR in standard clinical practice.