Managing clinically significant findings in research: the UK10K example.
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ABSTRACT:
SUBMITTER: Kaye J
PROVIDER: S-EPMC4026295 | biostudies-other | 2014 Sep
REPOSITORIES: biostudies-other
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Project description:BackgroundSyncope is a common reason for visiting the emergency department (ED) and is associated with significant healthcare resource utilization.ObjectiveTo develop a risk-stratification tool for clinically significant findings on echocardiography among older adults presenting to the ED with syncope or nearsyncope.DesignProspective, observational cohort study from April 2013 to September 2016.SettingEleven EDs in the United States.PatientsWe enrolled adults (=60 years) who presented to the ED with syncope or near-syncope who underwent transthoracic echocardiography (TTE).MeasurementsThe primary outcome was a clinically significant finding on TTE. Clinical, electrocardiogram, and laboratory variables were also collected. Multivariable logistic regression analysis was used to identify predictors of significant findings on echocardiography.ResultsA total of 3,686 patients were enrolled. Of these, 995 (27%) received echocardiography, and 215 (22%) had a significant finding on echocardiography. Regression analysis identified five predictors of significant finding: (1) history of congestive heart failure, (2) history of coronary artery disease, (3) abnormal electrocardiogram, (4) high-sensitivity troponin-T >14 pg/mL, and 5) N-terminal pro B-type natriuretic peptide >125 pg/mL. These five variables make up the ROMEO (Risk Of Major Echocardiography findings in Older adults with syncope) criteria. The sensitivity of a ROMEO score of zero for excluding significant findings on echocardiography was 99.5% (95% CI: 97.4%-99.9%) with a specificity of 15.4% (95% CI: 13.0%-18.1%).ConclusionsIf validated, this risk-stratification tool could help clinicians determine which syncope patients are at very low risk of having clinically significant findings on echocardiography.RegistrationClinicalTrials.gov Identifier NCT01802398.
| S-EPMC6343846 | biostudies-literature
Project description:BackgroundChromosomal microarray (CMA) is commonly utilized in the obstetrics setting. CMA is recommended when one or more fetal structural abnormalities is identified. CMA is also commonly used to determine genetic etiologies for miscarriages, fetal demise, and confirming positive prenatal cell-free DNA screening results.MethodsIn this study, we retrospectively examined 523 prenatal and 319 products-of-conception (POC) CMA cases tested at Nationwide Children's Hospital from 2011 to 2020. We reviewed the referral indications, the diagnostic yield, and the reported copy number variants (CNV) findings.ResultsIn our cohort, the diagnostic yield of clinically significant CNV findings for prenatal testing was 7.8% (n = 41/523) compared to POC testing (16.3%, n = 52/319). Abnormal ultrasound findings were the most common indication present in 81% of prenatal samples. Intrauterine fetal demise was the common indication identified in POC samples. The most common pathogenic finding observed in all samples was isolated trisomy 21, detected in seven samples.ConclusionOur CMA study supports the clinical utility of prenatal CMA for clinical management and identifying genetic etiology in POC arrays. In addition, it provides insight to the spectrum of prenatal and POC CMA results as detected in an academic hospital clinical laboratory setting that serves as a reference laboratory.
| S-EPMC10958178 | biostudies-literature
Project description:Next-generation sequencing (NGS) for tumor molecular profiling can reveal secondary germline pathogenic and likely pathogenic variants (LPV/PV). The American College of Medical Genetics (ACMG) recommends return of secondary results for a subset of 59 genes, but other genes with evidence of clinical utility are emerging. We previously reported that 4.3% of patients who underwent NGS of a targeted panel of 201 genes had LPV/PV based on the ACMG list. Here we report the frequency of additional germline cancer-related gene variants and discuss their clinical utility. Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in a research laboratory on samples from 1000 patients with advanced or metastatic solid tumors enrolled in a molecular testing protocol (NCT01772771). The frequency of germline LPV/PV in 54 cancer-related genes, beyond the genes in ACMG list, were analyzed. Among 1000 patients who underwent tumor/normal DNA sequencing, 46 (4.6%) were found to have a germline LPV/PV in the following genes: AR-(5), ATM-(4), BAP1-(1), CDH1-(1), CDKN2A-(1), CHEK1-(2), CHEK2-(10), EGFR-(1), ERCC3-(4), ERCC5-(1), HNF1B-(1), HRAS-(1), MITF-(4), MLL3-(1), NF1-(3), PKHD1-(4), PTCH1-(1), and SMARCA4-(1). Thus, a total 8.7% of patients had an LPV/PV with 2 patients having 2 concomitant germline LPV/PV. Five mutations in high-penetrance hereditary cancer predisposition genes were selected to be returned to patients or their representatives: BAP1, CDH1, CDKN2A, EGFR, and SMARCA4. Broader genomic testing is likely to identify additional secondary pathogenic germline alterations, some with potential clinical utility for return to patients and their relatives. The recommended genes for which germline results should be returned are continually changing, warranting continued study.
| S-EPMC6741435 | biostudies-literature
Project description:Previous studies have shown that mild traumatic brain injury (mTBI) can cause abnormalities in clinically relevant magnetic resonance imaging (MRI) sequences. No large-scale study, however, has prospectively assessed this in athletes with sport-related concussion (SRC). The aim of the current study was to characterize and compare the prevalence of acute, trauma-related MRI findings and clinically significant, non-specific MRI findings in athletes with and without SRC. College and high-school athletes were prospectively enrolled and participated in scanning sessions between January 2015 through August 2017. Concussed contact sport athletes (n = 138; 14 female [F]; 19.5 ± 1.6 years) completed up to four scanning sessions after SRC. Non-concussed contact (n = 135; 15 F; 19.7 ± 1.6) and non-contact athletes (n = 96; 15 F; 20.0 ± 1.7) completed similar scanning sessions and served as controls. Board-certified neuroradiologists, blinded to SRC status, reviewed T1-weighted and T2-weighted fluid-attenuated inversion recovery and T2*-weighted and T2-weighted images for acute (i.e., injury-related) or non-acute findings that prompted recommendation for clinical follow-up. Concussed athletes were more likely to have MRI findings relative to contact (30.4% vs. 15.6%; odds ratio [OR] = 2.32; p = 0.01) and non-contact control athletes (19.8%; OR = 2.11; p = 0.04). Female athletes were more likely to have MRI findings than males (43.2% vs. 19.4%; OR = 2.62; p = 0.01). One athlete with SRC had an acute, injury-related finding; group differences were largely driven by increased rate of non-specific white matter hyperintensities in concussed athletes. This prospective, large-scale study demonstrates that <1% of SRCs are associated with acute injury findings on qualitative structural MRI, providing empirical support for clinical guidelines that do not recommend use of MRI after SRC.
| S-EPMC6551984 | biostudies-literature
Project description:Those infected with the human immunodeficiency virus (HIV) have a greater risk of cardiovascular disease and might undergo computed tomographic (CT) scans for early detection. Incidental findings on cardiac CT imaging are important components of the benefits and costs of testing. We determined the prevalence and factors associated with incidental findings on CT scans performed to screen for coronary artery calcium (CAC) among HIV-infected men. A clinically significant finding was defined as requiring additional workup or a medical referral. A total of 215 HIV-infected men were evaluated. Their median age was 43 years; 17% were current tobacco users; the median CD4 count was 580 cells/mm(3); and 83% were receiving antiretroviral medications. Also, 34% had a positive CAC score of >0. An incidental finding was noted among 93 participants (43%), with 36 (17%) having ?1 clinically significant finding. A total of 139 findings were noted, most commonly pulmonary nodules, followed by granulomas, scarring, and hilar adenopathy. Most of the incidental findings were stable on follow-up, and no malignancies were detected. The factors associated with the presence of an incidental finding in the multivariate model included increasing age (odds ratio 1.6 per 10 years, p <0.01), positive CAC score (odds ratio 2.3, p <0.01), and current tobacco use (odds ratio 2.5, p = 0.02). In conclusion, incidental findings were common among HIV-infected men undergoing screening CT imaging for CAC determination. The incidental findings were more common among older patients and those with detectable CAC.
| S-EPMC3076059 | biostudies-literature
Project description:We have isolated two phenotypically distinct nonfastidious Francisella strains (Fx1 and Fx2) from the blood of compromised patients with pneumonia and compared them with eight other Francisella strains, including Francisella tularensis biovar tularensis, F. tularensis biovar novicida, and F. philomiragia. Our isolates grew well on sheep blood agar, chocolate agar, modified Thayer-Martin agar, and Trypticase soy agar. Fx1 and Fx2 were determined to be within the Francisella genus by cellular fatty acid analysis and by the utilization of glucose, production of H2S and catalase, and lack of motility, oxidase, nitrate reductase, and gelatinase. They were additionally shown to belong to the species F. tularensis by sequencing of two variable regions comprising approximately 500 nucleotides of the 16S rRNA gene. Also, RNA probe hybridization confirmed their belonging to the species F. tularensis. However, the new strains, which are not identical, are distinguished from other F. tularensis strains by growth characteristics, repetitive extragenic palindromic PCR fragment pattern, and some biochemical tests. Key biochemical differences included the findings that Fx1 was positive for beta-galactosidase and arabinose hydrolysis and that both strains were citrulline ureidase positive and glycerol negative. Commercial F. tularensis antiserum agglutinated stock F. tularensis strains but not Fx1, Fx2, F. tularensis biovar novicida, or F. philomiragia; serum from either patient failed to agglutinate or only weakly agglutinated commercial antigen but showed agglutination when tested against each patient's respective isolate. Fx1 and Fx2 produced beta-lactamase. Because of their good growth, negative serology, and biochemical profile, the organisms could be misidentified in the clinical laboratory if standard strategies or commercial identification systems are used.
| S-EPMC229169 | biostudies-other
Project description:Nanotechnology has played a crucial role in the development of biosensors over the past decade. The development, testing, optimization, and validation of new biosensors has become a highly interdisciplinary effort involving experts in chemistry, biology, physics, engineering, and medicine. The sensitivity, the specificity and the reproducibility of biosensors have improved tremendously as a result of incorporating nanomaterials in their design. In general, nanomaterials-based electrochemical immunosensors amplify the sensitivity by facilitating greater loading of the larger sensing surface with biorecognition molecules as well as improving the electrochemical properties of the transducer. The most common types of nanomaterials and their properties will be described. In addition, the utilization of nanomaterials in immunosensors for biomarker detection will be discussed since these biosensors have enormous potential for a myriad of clinical uses. Electrochemical immunosensors provide a specific and simple analytical alternative as evidenced by their brief analysis times, inexpensive instrumentation, lower assay cost as well as good portability and amenability to miniaturization. The role nanomaterials play in biosensors, their ability to improve detection capabilities in low concentration analytes yielding clinically useful data and their impact on other biosensor performance properties will be discussed. Finally, the most common types of electroanalytical detection methods will be briefly touched upon.
| S-EPMC5455914 | biostudies-other
Project description:OBJECTIVE:Advances in developmentally sensitive measurement have enabled differentiation of normative versus clinically salient irritability in early childhood. However, clinical application of these measures is still nascent. The authors developed an optimized model of clinically salient irritable behaviors at preschool age. Based on this model, the authors derived an empirically based cutoff in relation to concurrent DSM-5 irritability-related disorders (i.e., oppositional defiant disorder, disruptive mood dysregulation disorder, other depressive disorders) and used longitudinal models to test the predictive validity of the cutoff for impairment and irritability trajectories and later DSM disorders. METHOD:Preschool children oversampled for irritability were followed over 3 time points into early school age (N = 425; mean age at baseline 4.7 years, mean follow-up 2.9 years). Mothers reported on children's irritability using the developmentally validated Multidimensional Assessment of Profile of Disruptive Behavior (MAP-DB) Temper Loss scale, impairment using the Family Life Impairment Scale, and DSM categories using the Preschool Age Psychiatric Assessment and the Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. RESULTS:Of 22 MAP-DB Temper Loss behaviors, 2 behaviors-1 normative (easily frustrated) and 1 rare dysregulated (destructive tantrums)-were uniquely related to cross-domain impairment. At baseline, these 2 irritability items identified diagnostic status (oppositional defiant disorder, disruptive mood dysregulation disorder, other depressive disorders) with good sensitivity (70-73%) and specificity (74-83%). Children above the irritability cutoff at baseline also exhibited more persistent irritability and impairment and greater likelihood of DSM disorders in early school age. CONCLUSION:Clinical identification of early-onset irritability can be enhanced using brief, developmentally optimized indicators. Further research to apply these findings to tiered early intervention is important.
| S-EPMC5860673 | biostudies-literature
Project description:Purpose. To design and validate a prenatal chromosomal microarray testing strategy that moves away from size-based detection thresholds, towards a more clinically relevant analysis, providing higher resolution than G-banded chromosomes but avoiding the detection of copy number variants (CNVs) of unclear prognosis that cause parental anxiety. Methods. All prenatal samples fulfilling our criteria for karyotype analysis (n = 342) were tested by chromosomal microarray and only CNVs of established deletion/duplication syndrome regions and any other CNV >3 Mb were detected and reported. A retrospective full-resolution analysis of 249 of these samples was carried out to ascertain the performance of this testing strategy. Results. Using our prenatal analysis, 23/342 (6.7%) samples were found to be abnormal. Of the remaining samples, 249 were anonymized and reanalyzed at full-resolution; a further 46 CNVs were detected in 44 of these cases (17.7%). None of these additional CNVs were of clear clinical significance. Conclusion. This prenatal chromosomal microarray strategy detected all CNVs of clear prognostic value and did not miss any CNVs of clear clinical significance. This strategy avoided both the problems associated with interpreting CNVs of uncertain prognosis and the parental anxiety that are a result of such findings.
| S-EPMC4006225 | biostudies-literature
Project description:A set of prostate tumors tend to grow slowly and do not require active treatment. Therefore, stratification between patients with clinically significant and clinically insignificant prostate cancer (PC) remains a vital issue to avoid overtreatment. Fast development of genetic technologies accelerated development of next-generation molecular tools for reliable PC diagnosis. The aim of this study is to evaluate the diagnostic value of molecular biomarkers (CRISP3, LMTK2, and MSMB) for separation of PC cases from benign prostatic changes and more specifically for identification of clinically significant PC from all pool of PC cases in patients with rising PSA levels. Patients (n?=?200) who had rising PSA (PSA II) after negative transrectal systematic prostate biopsy due to elevated PSA (PSA I) were eligible to the study. In addition to PSA concentration, PSA density was calculated for each patient. Gene expression level was measured in peripheral blood samples of cases applying RT-PCR, while MSMB (-57?C/T) polymorphism was identified by pyrosequencing. LMTK2 and MSMB significantly differentiated control group from both BPD and PC groups. MSMB expression tended to increase from the major alleles of the CC genotype to the minor alleles of the TT genotype. PSA density was the only clinical characteristic that significantly differentiated clinically significant PC from clinically insignificant PC. Therefore, LMTK2 expression and PSA density were significantly distinguished between clinically significant PC and clinically insignificant PC. PSA density rather than PSA can differentiate PC from the benign prostate disease and, in combination with LMTK2, assist in stratification between clinically insignificant and clinically significant PC.
| S-EPMC7803409 | biostudies-literature