Guidelines For Interpretation Research Articles

Conceptualizing meaningful between-group difference in change over time: a demonstration of possible viewpoints.

Determining if group-level differences in health outcomes are meaningful has recently been neglected in favour of determining if individuals have experienced a meaningful change. We explore interpretation of a meaningful between-group difference (MBGD) in clinical outcome assessment scores, primarily in the context of randomized clinical trials. We constructed a series of possible 'viewpoints' on how to conceptualize MBGD thresholds. Each viewpoint is discussed critically in terms of potential advantages and disadvantages, with simulated data to facilitate their consideration. Five viewpoints are presented and discussed. The first considers whether thresholds for meaningful within-individual change over time can be equally applied at the group-level, which is shown to be untenable. Viewpoints 2-4 consider what would have to be observed in treatment groups to conclude a meaningful between-group difference has occurred, framed in terms of the proportion of patients perceiving that they had meaningfully improved. The final viewpoint considers an alternative framework where stakeholders are directly questioned on the meaningfulness of varying magnitudes of between-group differences. The choice of a single threshold versus general interpretative guidelines is discussed. There does not appear to be a single method with clear face validity for determining MBGD thresholds. Additionally, the notion that such thresholds can be purely data-driven is challenged, where a degree of subjective stakeholder judgement is likely required. Areas for future research are proposed, to move towards robust method development.

Implementation of an algorithm for testing, diagnosis, and antibiotic stewardship of asymptomatic bacteriuria in pregnancy

BackgroundAsymptomatic bacteriuria (ASB) affects 2-15% of pregnant women, with 20-40% developing symptoms later. Symptomatic urinary tract infections (UTIs) are more common in pregnancy, with a prevalence of 33%, posing risks like preterm delivery, low birth weight, and maternal pyelonephritis. The gold standard for UTI detection is a urine culture, but point-of-care urinalysis dipsticks are frequently performed as screens during regular obstetric visits. Leukocyte esterase has been used to justify treatment in the asymptomatic, even with low sensitivity and specificity. Confirmatory tests are crucial to avoid false positives and ensure optimal outcomes. Current guidelines for urinalysis dipstick interpretation and the decision to treat ASB in pregnancy are limited. It remains unclear if an evidence-based algorithm can improve test utilization, diagnosis, and treatment decisions for ASB in pregnancy. ObjectivesThe primary objective of our study is to develop, implement, and evaluate an evidence-based algorithm to guide urinalysis interpretation, culturing, diagnosis, and antibiotic stewardship of asymptomatic bacteriuria in pregnant patients during routine obstetric visits. Study DesignThe project involves both retrospective and quasi-experimental prospective chart reviews of pregnant patients aged 18 and older, beyond 20 weeks gestation, from routine obstetric visits with urinalysis dipstick tests. A doctorate in clinical laboratory sciences student developed an educational algorithm to guide urinalysis dipstick interpretation, culturing necessity, and treatment decisions based on evidence-based practice. Our study considered patient records from February 1 – 28, 2022 as retrospective (pre-algorithm implementation) data and January 24 - February 22, 2023, as prospective (post-algorithm implementation) data. Data collected from the electronic medical record included de-identified patient information, urinalysis results, culture dates and outcomes, antibiotic prescriptions, UTI or ASB diagnoses, provider details, adverse pregnancy outcomes, and demographics. Data analysis using SPSS version 29 involved chi-square tests, likelihood ratios, and effect size calculations, with P-values <0.05 considered statistically significant. ResultsIn our study, we examined a total of 1,176 patient records. Pre-implementation data included 440 records, with 224 abnormal and 216 normal urinalyses. Post-implementation data encompassed 736 records, of which 255 were abnormal and 481 were normal. The patient demographics predominantly featured White (87%), with a median maternal age of 27 years and a gestational age of 32 weeks. Our pre-implementation analyses revealed significant associations between algorithm deviations with both culture utilization (P <.001) and antibiotic stewardship (P <.001). However, no significant associations were observed between algorithm deviations and adverse patient outcomes. Culture underutilization decreased significantly from 43.0% (189/440) pre-implementation to 29.5% (217/736) post-implementation (P < .001). The overall reduction in ASB prevalence from 16.3% (8/49) to 6.7% (10/67) suggests a decrease of nearly 60%. Additionally, antibiotic overprescription decreased significantly from 1.6% (4/258) pre-implementation to 0.8% (4/522) post-implementation (P = .003), with a reduction from 7.1% (3/42) to 2.4% (1/41) among abnormal urinalyses. ConclusionOur findings show a strong alignment between the use of the algorithm and subsequent clinical decisions, underscoring its potential to enhance patient care and management in obstetric settings. Notably, adherence to the algorithm was higher among providers displaying prudent antibiotic use.

Functional characterization of all CDKN2A missense variants and comparison to in silico models of pathogenicity.

Interpretation of variants identified during genetic testing is a significant clinical challenge. In this study, we developed a high-throughput CDKN2A functional assay and characterized all possible CDKN2A missense variants. We found that 17.7% of all missense variants were functionally deleterious. We also used our functional classifications to assess the performance of in silico models that predict the effect of variants, including recently reported models based on machine learning. Notably, we found that all in silico models performed similarly when compared to our functional classifications with accuracies of 39.5-85.4%. Furthermore, while we found that functionally deleterious variants were enriched within ankyrin repeats, we did not identify any residues where all missense variants were functionally deleterious. Our functional classifications are a resource to aid the interpretation of CDKN2A variants and have important implications for the application of variant interpretation guidelines, particularly the use of in silico models for clinical variant interpretation.

Quality of life of women with a screen-detected versus clinically detected breast cancer in the Netherlands: a prospective cohort study.

Breast cancer (BC) screening enables early detection of BC, which may lead to improved quality of life (QoL). We aim to compare QoL between women with a screen-detected and clinically detected BC in the Netherlands. We used data from the 'Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation' (UMBRELLA) between October 2013 and March 2022. Patients were categorized as screen-detected or clinically detected. We analysed three questionnaires, namely EORTC QLQ C-30, BR23, and HADS (Hospital Anxiety and Depression Scale) completed by BC patients shortly after diagnosis (T1) and one-year after treatment (T2). Independent t-tests were performed to compare QoL average differences between the two groups. Bonferroni-corrected p-value significance threshold of 0.00057 was used. The magnitude of differences was calculated using Cohen's d. The clinical relevance of QLQ-C30 differences was assessed based on interpretation guideline of EORTC-QLQ-C30 results. After applying inclusion and exclusion criteria, there were 691 women with screen-detected BC and 480 with clinically detected BC. Generally, screen-detected BC patients reported a better QoL. At T1, their average QLQ-C30 summary score was higher (86.1) than clinically detected BC patients (83.0) (p < 0.0001). Cohen's d for all items ranged between 0.00 and 0.39. A few QLQ-C30 score differences were clinically relevant, indicating better outcomes in emotional functioning, general health, constipation, and fatigue for women with screen-detected BC. In the Netherlands, women with screen-detected BC reported statistically significant and better QoL than women with clinically detected BC. However, clinical relevance of the differences is limited.

Impact of comorbidity on health-related quality of life in newly diagnosed patients with lymphoma or multiple myeloma: results from the PROFILES-registry.

With the increasing prevalence of comorbidity in an ageing population, it is crucial to better understand the impact of comorbidity on health-related quality of life (HRQoL) after lymphoma or multiple myeloma (MM) diagnosis. We included 261 newly diagnosed patients (67% response rate) diagnosed with lymphoma or MM between October 2020 and March 2023 in a longitudinal survey. The European Organisation for Research and Treatment of Cancer (EORTC) questionnaires were used to measure generic and disease-specific HRQoL. Evidence-based guidelines for interpretation of the EORTC questionnaires were used to identify clinical importance. Patients were classified as having 'no comorbidity', 'mild comorbidity' (e.g. arthrosis or rheumatism), or 'moderate-severe comorbidity' (e.g. heart or lung disease), using the adapted self-administered comorbidity questionnaire. At diagnosis, the mean age was 64 years, 63% were male and 38% reported no comorbidity, 33% mild comorbidity, and 29% moderate-severe comorbidity. Patients with mild or moderate-severe comorbidity reported clinically relevant worse HRQoL at diagnosis than patients without comorbidity. One year post-diagnosis most outcomes showed clinically relevant improvement, irrespective of comorbidity. However, outcomes of physical functioning (β=-7.9, p < 0.05), global health status (β=-7.6, p < 0.05), bone pain (β = 8.1 to 9.1, p < 0.05), muscle/joint pain (β = 14.5 to 18.8, p < 0.01) and muscle weakness (β = 10.4 to 15.6, p < 0.05) improved less among those with comorbidity, and clinically relevant differences between comorbidity groups persisted over time. With clinically relevant worse HRQoL at diagnosis and less recovery of HRQoL during the first year after diagnosis in patients with comorbidity, consideration of both prognosis and HRQoL is important when making treatment decisions.

Orthostatic testing for heart rate and heart rate variability monitoring in exercise science and practice.

Orthostatic testing, involving the transition from different body positions (e.g., from lying or sitting position to an upright or standing position), offers valuable insights into the autonomic nervous system (ANS) functioning and cardiovascular regulation reflected through complex adjustments in, e.g., measures of heart rate (HR) and heart rate variability (HRV). This narrative review explores the intricate physiological mechanisms underlying orthostatic stress responses and evaluates its significance for exercise science and sports practice. Into this matter, active orthostatic testing (e.g., active standing up) challenges the cardiovascular autonomic function in a different way than a passive tilt test. It is well documented that there is a transient reduction in blood pressure while standing up, leading to a reflex increase in HR and peripheral vasoconstriction. After that acute response systolic and diastolic blood pressures are usually slightly increased compared to supine lying body position. The ANS response to standing is initiated by instantaneous cardiac vagal withdrawal, followed by sympathetic activation and vagal reactivation over the first 25-30 heartbeats. Thus, HR increases immediately upon standing, peaking after 15-20 beats, and is less marked during passive tilting due to the lack of muscular activity. Standing also decreases vagally related HRV indices compared to the supine position. In overtrained endurance athletes, both parasympathetic and sympathetic activity are attenuated in supine and standing positions. Their response to standing is lower than in non-overtrained athletes, with a tendency for further decreased HRV as a sign of pronounced vagal withdrawal and, in some cases, decreased sympathetic excitability, indicating a potential overtraining state. However, as a significant main characteristic, it could be noted that additional pathophysiological conditions consist in a reduced responsiveness or counter-regulation of neural drive in ANS according to an excitatory stimulus, such as an orthostatic challenge. Hence, especially active orthostatic testing could provide additional information about HR(V) reactivity and recovery giving valuable insights into athletes' training status, fatigue levels, and adaptability to workload. Measuring while standing might also counteract the issue of parasympathetic saturation as a common phenomenon especially in well-trained endurance athletes. Data interpretation should be made within intra-individual data history in trend analysis accounting for inter-individual variations in acute responses during testing due to life and physical training stressors. Therefore, additional measures (e.g., psychometrical scales) are required to provide context for HR and HRV analysis interpretation. However, incidence of orthostatic intolerance should be evaluated on an individual level and must be taken into account when considering to implement orthostatic testing in specific subpopulations. Recommendations for standardized testing procedures and interpretation guidelines are developed with the overall aim of enhancing training and recovery strategies. Despite promising study findings in the above-mentioned applied fields, further research, thorough method comparison studies, and systematic reviews are needed to assess the overall perspective of orthostatic testing for training monitoring and fine-tuning of different populations in exercise science and training.

Urinary tract infection among people living with human immunodeficiency virus attending selected hospitals in Addis Ababa and Adama, central Ethiopia.

Urinary tract infections (UTIs) and antibacterial resistance (ABR) are important public health problems, but they are not well-studied among people living with human immunodeficiency virus (PLHIV) globally, especially in low-income countries. Therefore, it is important to regularly measure the extent of UTIs and ABR in the most susceptible populations. This study aimed to investigate the prevalence of UTIs, associated factors, bacterial causal agents, and their antibiotic susceptibility profile among PLHIV in central Ethiopia. A hospital-based cross-sectional study was conducted to recruit 688 PLHIV by a simple random sampling method. Background information was gathered through interviews, while clinical information was gathered from recent information sheets of patient charts using organized, pretested, and validated study tools. Midstream urine was collected aseptically and transported to the Microbiology Laboratory of Aklilu Lemma Institute of Pathobiology within 4 h of collection, maintaining its cold chain. Standard conventional microbial culture methods and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry were used to identify the bacterial isolates at the species level. Kirby Bauer's disk diffusion method was used to determine the antibiotic susceptibility profile of the bacterial isolates based on the interpretation guidelines of the Clinical Laboratory Standard Institute. Logistic regression models were used to examine factors associated with the occurrence of UTIs among PLHIV attending selected hospitals in Addis Ababa, and Adama. Out of 688 PLHIVs involved in the current study, 144 (20.9%) were positive for UTIs, whereas the majority were asymptomatic for UTIs. In the multivariable logistic regression analysis, only HIV RNA ≥ 200 copies/ml [AOR = 12.24 (95% CI, 3.24, 46.20), p < 0.01] and being symptomatic for UTIs during the study period [AOR = 11.57 (95% CI, 5.83, 22.97), p < 0.01] were associated with the occurrence of UTIs. The dominant bacterial species isolated were Escherichia coli (E. coli; n = 65; 43%), followed by Enterococcus faecalis (E. faecalis; n = 16; 10.6%) and Klebsiella pneumoniae (K. pneumoniae; n = 11; 7.3%). Over half of the E. coli isolates were resistant to antibiotics such as gentamicin (GM; n = 44; 67.7%), amikacin (AN; n = 46; 70.8%), nalidixic acid (NA; n = 42; 64.6%), ciprofloxacin (CIP; n = 40; 61.5%), and azithromycin (AZM; n = 45; 69.2%). All of the K. pneumoniae isolates (n = 11; 100%), (n = 6; 54.5%), and (n = 7; 63.6%) were resistant to [amoxicillin as well as amoxicillin + clavulanic acid], ceftriaxone, and sulfamethoxazole + trimethoprim, respectively. All the Staphylococcus aureus (S. aureus) isolates were resistant to cefoxitin, which implies methicillin-resistant S. aureus (MRSA). The high prevalence of UTIs and antibiotic resistance revealed in the current study needs public health interventions such as educating the population about preventive measures and the importance of early treatment of UTIs. Our findings also highlight the need to provide UTI screening services for PLHIV, and healthcare providers should adopt antibiotic stewardship programs to promote and ensure their appropriate and judicious use.

Movie Titles’ Translation Strategies from English into Thai in Monomax Application

The objective of this study is to analyze the strategies employed in translating English movie titles into Thai within the Monomax Application. A total of 501 English movie titles spanning the decade of 2011 and 2020 were examined because a decade provides clear guidelines for data collection, analysis, and interpretation. The strategies for translating film titles into Thai conducted by Thongwan (2012) served as a framework for this study. The findings revealed that all 10 translation strategies were employed as follows respectively: 1) naming a new name regardless of the old name, 2) naming a new name based on the original name, 3) partial translation and adding Thai language, 4) partial transliteration and adding Thai language, 5) all translation and adding Thai language, 6) all transliteration and adding Thai language, 7) all transliteration without adding Thai, and 8) all translation without adding Thai language. Meanwhile, the last two which are 9) partial transliteration without adding the Thai language and partial translation without adding the Thai language were found used only once per each. Notably, the translated movie titles in Thai often featured distinctive and attractive elements, such as rhyme and alliteration. These findings corresponded to Nida &amp; Taber (1974) translation theory that translation process is related to purpose and cultural linguistic norms. Future studies could explore the reception and perception of these translated titles among Thai audiences, shedding light on which strategies resonate most effectively and why.

A short scale to measure health-related quality of life after traumatic brain injury in children and adolescents (QOLIBRI-OS-KID/ADO): psychometric properties and German reference values.

The impact of pediatric traumatic brain injury (pTBI) on health-related quality of life (HRQoL) in children and adolescents remains understudied. Short scales have some advantages in terms of economy and administration over longer scales, especially in younger children. The aim of the present study is to psychometrically evaluate the six-item German version of the QOLIBRI-OS-KID/ADO scale for children and adolescents. In addition, reference values from a general German pediatric population are obtained to assist clinicians and researchers in the interpretation of HRQoL after pTBI. A total of 297 individuals after TBI and 1997 from a general population sample completed the questionnaire. Reliability, validity, and comparability of the assessed construct were examined. The questionnaire showed satisfactory reliability (α = 0.75 and ω = 0.81 and α = 0.85 and ω = 0.86 for the TBI and general population samples, respectively). The QOLIBRI-OS-KID/ADO was highly correlated with its long version (R2 = 67%) and showed an overlap with disease-specific HRQoL (R2 = 55%) in the TBI sample. The one-dimensional factorial structure could be replicated and tested for measurement invariance between samples, indicating a comparable HRQoL construct assessment. Therefore, reference values and cut-offs indicating clinically relevant impairment could be provided using percentiles stratified by factors significantly associated with the total score in the regression analyses (i.e., age group and gender). In combination with the cut-offs, the QOLIBRI-OS-KID/ADO provides a cost-effective screening tool, complemented by interpretation guidelines, which may help to draw clinical conclusions and indications such as further administration of a longer version of the instrument to gain more detailed insight into impaired HRQoL domains or omission of further steps in the absence of an indication.

Rationale and Design of the Australasian Registry of Screening ECGs in National Athletes Project.

Cardiac screening of elite athletes is widely recommended by Australasian sporting federations, but data are not structured to be shared. Data are lacking from underrepresented groups to inform ECG interpretation guidelines. The ARENA (Australasian Registry of Screening ECGs in National Athletes) project is a retrospective and prospective, multicenter, longitudinal, observational registry of athlete cardiac screening results and outcomes. The aim is to create a repository to improve our understanding of the diagnoses and outcomes of screening. Participating sports that conduct cardiac screening of athletes will contribute data. This includes an initial collection (retrospective data, waiver of consent) and future prospective data (opt-out consent). Data include sex, age, sport/event, screening date, ECG findings, cardiac test results, follow-up details, sport participation status, cardiac diagnoses, and major cardiovascular outcomes defined as sudden cardiac arrest/death, cardiac syncope or implanted cardioverter defibrillator shock, cardiac hospitalization, and arrhythmias requiring intervention. Comparisons will be made between diagnoses, outcomes, and ECG features and analyzed by sport and sex. The ARENA project was developed in collaboration with sporting bodies, team physicians, and players association representatives and endorsed by the Australasian College of Sport & Exercise Physicians and Sports Medicine Australia. The ARENA project will provide a long-term international data repository to improve our understanding of ECG interpretation, cardiac screening and diagnoses, and the prevalence of cardiovascular outcomes in screened athletes. A unique aim is to address evidence gaps in underrepresented athlete groups, specifically female athletes and Indigenous populations. Results will inform screening policies and guidelines.

Investigating current clinical opinions in stereoelectroencephalography-informed epilepsy surgery.

Stereoelectroencephalography (SEEG) is increasingly utilized worldwide in epilepsy surgery planning. International guidelines for SEEG terminology and interpretation are yet to be proposed. There are worldwide differences in SEEG definitions, application of features in epilepsy surgery planning, and interpretation of surgical outcomes. This hinders the clinical interpretation of SEEG findings and collaborative research. We aimed to assess the global perspectives on SEEG terminology, differences in the application of presurgical features, and variability in the interpretation of surgery outcome scores, and analyze how clinical expert demographics influenced these opinions. We assessed the practices and opinions of epileptologists with specialized training in SEEG using a survey. Data were qualitatively analyzed, and subgroups were examined based on geographical regions and years of experience. Primary outcomes included opinions on SEEG terminology, features used for epilepsy surgery, and interpretation of outcome scores. Additionally, we conducted a multilevel regression and poststratification analysis to characterize the nonresponders. A total of 321 expert responses from 39 countries were analyzed. We observed substantial differences in terminology, practices, and use of presurgical features across geographical regions and SEEG expertise levels. The majority of experts (220, 68.5%) favored the Lüders epileptogenic zone definition. Experts were divided regarding the seizure onset zone definition, with 179 (55.8%) favoring onset alone and 135 (42.1%) supporting onset and early propagation. In terms of presurgical SEEG features, a clear preference was found for ictal features over interictal features. Seizure onset patterns were identified as the most important features by 265 experts (82.5%). We found similar trends after correcting for nonresponders using regression analysis. This study underscores the need for standardized terminology, interpretation, and outcome assessment in SEEG-informed epilepsy surgery. By highlighting the diverse perspectives and practices in SEEG, this research lays a solid foundation for developing globally accepted terminology and guidelines, advancing the field toward improved communication and standardization in epilepsy surgery.

39. Modifying cancer variant interpretation guidelines for the curation of histone H3 variants: The 'next step' of the Cl

39. Modifying cancer variant interpretation guidelines for the curation of histone H3 variants: The 'next step' of the Cl

Genetic Diversity in Salmonella enterica in Outbreaks of Foodborne and Zoonotic Origin in the USA in 2006-2017.

Whole genome sequencing is replacing traditional laboratory surveillance methods as the primary tool to track and characterize clusters and outbreaks of the foodborne and zoonotic pathogen Salmonella enterica (S. enterica). In this study, 438 S. enterica isolates representing 35 serovars and 13 broad vehicle categories from one hundred epidemiologically confirmed outbreaks were evaluated for genetic variation to develop epidemiologically relevant interpretation guidelines for Salmonella disease cluster detection. The Illumina sequences were analyzed by core genome multi-locus sequence typing (cgMLST) and screened for antimicrobial resistance (AR) determinants and plasmids. Ninety-three of the one hundred outbreaks exhibited a close allele range (less than 10 allele differences with a subset closer than 5). The remaining seven outbreaks showed increased variation, of which three were considered polyclonal. A total of 16 and 28 outbreaks, respectively, showed variations in the AR and plasmid profiles. The serovars Newport and I 4,[5],12:i:-, as well as the zoonotic and poultry product vehicles, were overrepresented among the outbreaks, showing increased variation. A close allele range in cgMLST profiles can be considered a reliable proxy for epidemiological relatedness for the vast majority of S. enterica outbreak investigations. Variations associated with mobile elements happen relatively frequently during outbreaks and could be reflective of changing selective pressures.

PRECAUTIONARY MEASURE AGAINST INDIGENOUS PERSONS IN ECUADOR: AN ANALYSIS OF ITS CULTURAL AND LEGAL APPROPRIATENESS

Objetive: This article analyzes the appropriateness of pretrial detention when used as a precautionary measure in criminal procedures against Indigenous persons in Ecuador. Theoretical structure: The theoretical framework is based on the doctrine of criminal guarantees and the conventional obligations of the Ecuadorian state, mainly from inter-American jurisprudence. The discussion is complemented by a critical analysis of positivism and the persistence of the colonialist vision in the institutionality of the criminal justice system. Method: A doctrinal and jurisprudential approach is carried out, which is complemented with an analysis based on the ethnographic approach and interpretation of the normative as discourse. Conclusion: With regard to pretrial detention, Inter-American law has developed standards that will be analyzed in the framework of cultural diversity, seeking to establish a few guidelines for an intercultural interpretation, in which Indigenous authorities may participate in the precautionary guarantees. Therefore, the Constitutional Court of Ecuador has rendered many judgments that adhere to intercultural guidelines for cases and trials against Indigenous peoples and nationalities.

Unsupervised Machine Learning‐Derived Anion‐Exchange Membrane Polymers Map: A Guideline for Polymers Exploration and Design

AbstractAlthough anion‐exchange membranes (AEMs) are commonly used in fuel cells and water electrolyzers, their widespread commercialization is hindered by problems such as low anion conductivity and durability. Moreover, the development of high‐performance AEMs remains complex and time consuming. Here, we address these challenges by proposing an innovative approach for the efficient design and screening of AEM polymers using unsupervised machine learning. Our model, which combines principal component analysis with uniform manifold approximation and projection, generates an intuitive map that clusters AEM polymers based on structural similarities without any predefined knowledge regarding anion conductivity or other experimentally derived variables. As a powerful navigation tool, this map provides insights into promising main‐chain structures, such as poly(arylene alkylene)s with consistently high conductivity and polyolefins with exceptional performance depending on the substituent. Furthermore, assisted by key molecular descriptors, inverse analysis with this model allows targeted design and property prediction before synthesis, which will significantly accelerate the discovery of novel AEM polymers. This work represents a paradigm shift not only in AEM research but also generally in materials research, moving from black‐box predictions toward interpretable guidelines that foster collaboration between researchers and machine learning for efficient and informed material development.

Pathogen-Agnostic Advanced Molecular Diagnostic Testing for Difficult-to-Diagnose Clinical Syndromes-Results of an Emerging Infections Network Survey of Frontline US Infectious Disease Clinicians, May 2023.

During routine clinical practice, infectious disease physicians encounter patients with difficult-to-diagnose clinical syndromes and may order advanced molecular testing to detect pathogens. These tests may identify potential infectious causes for illness and allow clinicians to adapt treatments or stop unnecessary antimicrobials. Cases of pathogen-agnostic disease testing also provide an important window into known, emerging, and reemerging pathogens and may be leveraged as part of national sentinel surveillance. A survey of Emerging Infections Network members, a group of infectious disease providers in North America, was conducted in May 2023. The objective of the survey was to gain insight into how and when infectious disease physicians use advanced molecular testing for patients with difficult-to-diagnose infectious diseases, as well as to explore the usefulness of advanced molecular testing and barriers to use. Overall, 643 providers answered at least some of the survey questions; 478 (74%) of those who completed the survey had ordered advanced molecular testing in the last two years, and formed the basis for this study. Respondents indicated that they most often ordered broad-range 16S rRNA gene sequencing, followed by metagenomic next-generation sequencing and whole genome sequencing; and commented that in clinical practice, some, but not all tests were useful. Many physicians also noted several barriers to use, including a lack of national guidelines and cost, while others commented that whole genome sequencing had potential for use in outbreak surveillance. Improving frontline physician access, availability, affordability, and developing clear national guidelines for interpretation and use of advanced molecular testing could potentially support clinical practice and public health surveillance.

P-566 Addressing ethnic underrepresentation in carrier screening: prioritizing comprehensive variant curation over ClinVar-based automated analysis

Abstract Study question How does the use of a ClinVar-based approach in Carrier Genetic Screening (CGS) affect the efficiency and accuracy of carrier detection analysis? Summary answer For CGS, comprehensive variant curation, not automated analysis alone, addresses risk from under-representation of diverse populations in genetic databases. What is known already Next-generation sequencing (NGS) analyses in Carrier Screening (CS) yield numerous variants per patient requiring interpretation for pathogenicity assessment. Public variant databases aid in the curation process, clinical interpretation, and genomic data sharing, reducing error risks and diagnostic delays. Consequently, an increasing number of genetic laboratories are integrating these databases into their workflows. However, over-representation of certain ethnic groups persists due to genetic inequality, as these databases primarily contain variants previously reported in patients and manually recorded. This lack of ethnic diversity in human genomic studies and databases can lead to inaccurate risk assessment and inadequate interventions in under-studied populations. Study design, size, duration Retrospective analysis involved 3886 patients of various ethnicities examined between June 2021 and March 2023. They were grouped according to self-reported ethnicity: African(54), Asian(43), Mediterranean(689), European/Caucasian(2402), Latino(449) and not reported(249). Participants/materials, setting, methods Patients were categorized based on their self-reported ethnicity after undergoing analysis with a Carrier Screening (CS) panel of 300 genes, which included autosomal recessive and X-linked disorders, using Next-Generation Sequencing (NGS). Complete variant curation (CCV) was conducted using the American College of Medical Genetics and Genomics(ACMG) and ClinGen guidelines for variant interpretation. The average number of variants per patient was calculated for both the automated process using only the ClinVar database and the CCV performed. Main results and the role of chance Upon evaluating the number of variants identified per patient,, 1.51 variants/patient (v/p) were observed when CCV, while 1.27 v/p would have been detected using only ClinVar (automated process). In summary, ClinVar accounted for 88% of all variants identified with CCV. Significant differences in variant detection were observed across ethnicities. The percentage of variants not detected by the automatic process were as follows: 21.95% in Asian ethnicity, 17.84% in African, 13.99% in Latino, 11.88% in Mediterranean, 10.97% in European/Caucasian and 10.70% in patients who did not report ethnicity. Among these, Asian and African ethnic groups had the lowest percentage of variants detected by ClinVar 78.05% and 82.16%, respectively. In the Asian group, 0.95 v/p were identified, while in the African group, 1.70 v/p were identified. Limitations, reasons for caution Data was collected based on self-reported ethnicity, which may not always accurately reflect true ancestry. Additionally, the sample size for certain ethnicities was relatively small. Variant classification relied on information available in databases or literature at the time of the study, potentially subject to updates or revisions in the future. Wider implications of the findings This study underscores the limitations of automated analysis in detecting all variants identified by CCV across ethnicities, highlighting genetic disparities present in mutation databases like ClinVar. The findings emphasize the importance of implementing CCV in Carrier Screening tests to effectively mitigate reproductive risks across diverse ethnic groups. Trial registration number not applicable

Provision and evaluation of explanations within an automated planning-based approach to solving the multimorbidity problem

The multimorbidity problem involves the identification and mitigation of adverse interactions that occur when multiple computer interpretable guidelines are applied concurrently to develop a treatment plan for a patient diagnosed with multiple diseases. Solving this problem requires decision support approaches which are difficult to comprehend for physicians. As such, the rationale for treatment plans generated by these approaches needs to be provided. Objective:To develop an explainability component for an automated planning-based approach to the multimorbidity problem, and to assess the fidelity and interpretability of generated explanations using a clinical case study. Methods:The explainability component leverages the task-network model for representing computer interpretable guidelines. It generates post-hoc explanations composed of three aspects that answer why specific clinical actions are in a treatment plan, why specific revisions were applied, and how factors like medication cost, patient’s adherence, etc. influence the selection of specific actions. The explainability component is implemented as part of MitPlan, where we revised our planning-based approach to support explainability. We developed an evaluation instrument based on the system causability scale and other vetted surveys to evaluate the fidelity and interpretability of its explanations using a two dimensional comparison study design. Results:The explainability component was implemented for MitPlan and tested in the context of a clinical case study. The fidelity and interpretability of the generated explanations were assessed using a physician-focused evaluation study involving 21 participants from two different specialties and two levels of experience. Results show that explanations provided by the explainability component in MitPlan are of acceptable fidelity and interpretability, and that the clinical justification of the actions in a treatment plan is important to physicians. Conclusion:We created an explainability component that enriches an automated planning-based approach to solving the multimorbidity problem with meaningful explanations for actions in a treatment plan. This component relies on the task-network model to represent computer interpretable guidelines and as such can be ported to other approaches that also use the task-network model representation. Our evaluation study demonstrated that explanations that support a physician’s understanding of the clinical reasons for the actions in a treatment plan are useful and important.

Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases

BackgroundAs gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa...

Determination of angle of impact and directionality of drip stains on various fabrics

Bloodstain pattern analysis (BPA) on absorbent surfaces, such as fabrics, is far more complex compared to its application on smooth, hard, non-porous surfaces. Angle of impact and directionality are commonly interpreted from bloodstains but may be adversely affected by porous surfaces. In fact, there is a lack of evidence that traditional approaches to BPA are even applicable when blood impacts absorbent materials such as clothing and other fabrics. Hence, there is a critical need for research focusing on the validity and reliability of methods for bloodstain pattern analysis on textiles. Here, human blood drops were deposited on six different fabric types (cotton, satin polyester, rayon, blended polyester/spandex, blended nylon/spandex, and blended modal/polyester/spandex) at two known impact angles: 30° and 10°. Bloodstain morphology was found to be unique for each fabric. Calculated angles of impact for cotton and satin polyester were not statistically different from the known angle of impact while blended polyester/spandex, blended nylon/spandex, and blended modal/polyester/spandex significantly underestimated the known angle of impact. Even when stain morphology on fabric resembled those on a glass control, the angle of impact significantly underestimated the known. The ability to assign directionality based upon bloodstain morphology was dependent on the fabric type. These findings support the need for further research and the development of guidelines for bloodstain pattern interpretation on fabric materials.