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The Journal of Allergy and Clinical... Oct 2022Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. (Review)
Review
BACKGROUND
Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges.
OBJECTIVES
This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health.
METHODS
This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity.
RESULTS
Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option.
CONCLUSIONS
This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.
Topics: Exome; Female; Genetic Testing; Genomics; Humans; Male; Phenotype; Prospective Studies
PubMed: 35753512
DOI: 10.1016/j.jaci.2022.06.009 -
Genome Medicine Jan 2023Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic...
BACKGROUND
Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans.
METHODS
We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant.
RESULTS
We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders.
CONCLUSIONS
Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.
Topics: Child; Child, Preschool; Female; Humans; Male; Exome; Genetic Testing; Genomics; Middle East; Rare Diseases; Adolescent; Young Adult; Adult
PubMed: 36703223
DOI: 10.1186/s13073-023-01157-8 -
Genetics in Medicine : Official Journal... Jan 2021To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease.
PURPOSE
To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease.
METHODS
We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia.
RESULTS
ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%).
CONCLUSION
In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.
Topics: Adult; Australia; Child; Exome; Genetic Testing; Humans; Kidney Diseases; Exome Sequencing
PubMed: 32939031
DOI: 10.1038/s41436-020-00963-4 -
Clinical Microbiology and Infection :... Sep 2018Despite the development of new microbiologic technologies, blood cultures (BCs) remain the first-line tool for the diagnosis of bloodstream infections. Their diagnostic... (Review)
Review
BACKGROUND
Despite the development of new microbiologic technologies, blood cultures (BCs) remain the first-line tool for the diagnosis of bloodstream infections. Their diagnostic value may be affected when a microorganism of questionable evidence is isolated-for example, coagulase-negative staphylococci, Bacillus spp., viridans group streptococci, Corynebacterium spp., Propionibacterium spp. and Micrococcus spp. Finally, making a correct diagnosis of pathogenicity (vs. contamination) is challenging.
AIMS
To review the current ways of dealing with the problem of BC contaminants (BCCs) and to provide practical suggestions to decrease BCC rates.
SOURCES
PubMed electronic databases and existing reviews were searched up to December 2017 to retrieve relevant publications related to the topic.
CONTENTS
This review describes the burden of BCC and analyses the main current issues and controversies in interpreting the occurrence of potential BC contaminants. It focuses on the best-described approaches to decide whether BCC is present and discusses the different strategies of prevention in adults.
IMPLICATIONS
Each institution should have an efficient policy to prevent BCC, emphasizing the importance of following guidelines for prescribing and collecting BCs. Training healthcare workers should focus on detrimental influence on patient care and highlight the work and costs due to contaminants. The accurate differentiation of a contaminant from a true pathogen relies on a multidisciplinary approach and the clinical judgement of experienced practitioners.
Topics: Bacteriological Techniques; Blood Culture; Clinical Laboratory Services; Health Personnel; Humans
PubMed: 29621616
DOI: 10.1016/j.cmi.2018.03.030 -
Circulation. Genomic and Precision... Oct 2018Genomic variants associated with inherited cardiac conditions yet detected incidentally (‘secondary findings’) are likely to arise with increasing frequency as... (Review)
Review
Genomic variants associated with inherited cardiac conditions yet detected incidentally (‘secondary findings’) are likely to arise with increasing frequency as genome sequencing transitions into clinical practice. Since genotyping has until recently been directed by clinical diagnosis, assessment and management of individuals found to harbour such a variant as a secondary finding is unclear. Here we illustrate some diagnostic and psychosocial complexities of inherited cardiac condition secondary findings, exemplified by disclosure of a pathogenic variant in , associated with long QT syndrome, to a healthy male enrolled in diagnostic genome sequencing as an unaffected relative. This early case represents a shift from ‘phenotype-to-genotype’ to ‘genotype-to-phenotype’; we describe clinical evaluation, family history and a qualitative research interview with the secondary finding recipient, discuss the role of specialist services in variant interpretation, genetic counselling and clinical assessment, and some challenges of realising improved health outcomes following disclosure of a secondary finding.
Topics: Genetic Testing; Genotype; Humans; Long QT Syndrome; Mutation
PubMed: 30354302
DOI: 10.1161/CIRCGEN.118.002316 -
Epileptic Disorders : International... Oct 2022Epilepsy genetics is a rapidly developing field, in which novel disease-associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches...
Epilepsy genetics is a rapidly developing field, in which novel disease-associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre- and post-test counseling, and follow-up after genetic testing is completed. We acknowledge that the resources vary across different settings but highlight that genetic diagnostic testing for epilepsy should be prioritized when the likelihood of an informative finding is high. Results of genetic testing, in particular the identification of causative genetic variants, are likely to improve individual care. We emphasize the importance of genetic testing for individuals with epilepsy as we enter the era of precision therapy.
Topics: Diagnostic Techniques and Procedures; Epilepsy; Genetic Testing; Humans
PubMed: 35830287
DOI: 10.1684/epd.2022.1448 -
Swiss Medical Weekly 2015Overdiagnosis is the diagnosis of an abnormality that is not associated with a substantial health hazard and that patients have no benefit to be aware of. It is neither... (Review)
Review
Overdiagnosis is the diagnosis of an abnormality that is not associated with a substantial health hazard and that patients have no benefit to be aware of. It is neither a misdiagnosis (diagnostic error), nor a false positive result (positive test in the absence of a real abnormality). It mainly results from screening, use of increasingly sensitive diagnostic tests, incidental findings on routine examinations, and widening diagnostic criteria to define a condition requiring an intervention. The blurring boundaries between risk and disease, physicians' fear of missing a diagnosis and patients' need for reassurance are further causes of overdiagnosis. Overdiagnosis often implies procedures to confirm or exclude the presence of the condition and is by definition associated with useless treatments and interventions, generating harm and costs without any benefit. Overdiagnosis also diverts healthcare professionals from caring about other health issues. Preventing overdiagnosis requires increasing awareness of healthcare professionals and patients about its occurrence, the avoidance of unnecessary and untargeted diagnostic tests, and the avoidance of screening without demonstrated benefits. Furthermore, accounting systematically for the harms and benefits of screening and diagnostic tests and determining risk factor thresholds based on the expected absolute risk reduction would also help prevent overdiagnosis.
Topics: Asymptomatic Diseases; Defensive Medicine; Diagnostic Services; Early Detection of Cancer; Early Diagnosis; Ethics, Medical; Guidelines as Topic; Humans; Incidental Findings; Neoplasms; Physician-Patient Relations; Unnecessary Procedures
PubMed: 25612105
DOI: 10.4414/smw.2015.14060 -
Journal of Clinical Laboratory Analysis Jan 2018Organizing work flow is a major task of laboratory management. Recently, clinical laboratories have started to adopt methodologies such as Lean Six Sigma and some...
BACKGROUND
Organizing work flow is a major task of laboratory management. Recently, clinical laboratories have started to adopt methodologies such as Lean Six Sigma and some successful implementations have been reported. This study used Lean Six Sigma to simplify the laboratory work process and decrease the turnaround time by eliminating non-value-adding steps.
METHODS
The five-stage Six Sigma system known as define, measure, analyze, improve, and control (DMAIC) is used to identify and solve problems. The laboratory turnaround time for individual tests, total delay time in the sample reception area, and percentage of steps involving risks of medical errors and biological hazards in the overall process are measured.
RESULTS
The pre-analytical process in the reception area was improved by eliminating 3 h and 22.5 min of non-value-adding work. Turnaround time also improved for stat samples from 68 to 59 min after applying Lean. Steps prone to medical errors and posing potential biological hazards to receptionists were reduced from 30% to 3%.
CONCLUSION
Successful implementation of Lean Six Sigma significantly improved all of the selected performance metrics. This quality-improvement methodology has the potential to significantly improve clinical laboratories.
Topics: Clinical Laboratory Services; Diagnostic Errors; Humans; Quality Improvement; Time Factors; Total Quality Management; Workflow
PubMed: 28205271
DOI: 10.1002/jcla.22180 -
American Journal of Human Genetics Jul 2023Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such...
Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such findings, and the downstream medical efforts in response to discovery of unanticipated genetic risk variants, are lacking. From a clinical trial of comprehensive exome sequencing in 127 apparently healthy infants and 32 infants in intensive care, we previously identified 17 infants (10.7%) with unanticipated monogenic disease risks (uMDRs). In this analysis, we assessed actionability for each of these uMDRs with a modified ClinGen actionability semiquantitative metric (CASQM) and created radar plots representing degrees of penetrance of the condition, severity of the condition, effectiveness of intervention, and tolerability of intervention. In addition, we followed each of these infants for 3-5 years after disclosure and tracked the medical actions prompted by these findings. All 17 uMDR findings were scored as moderately or highly actionable on the CASQM (mean 9, range: 7-11 on a 0-12 scale) and several distinctive visual patterns emerged on the radar plots. In three infants, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 infants, uMDRs provided risk stratification for future medical surveillance. In 13 infants, uMDRs prompted screening for at-risk family members, three of whom underwent cancer-risk-reducing surgeries. Although assessments of clinical utility and cost-effectiveness will require larger datasets, these findings suggest that large-scale comprehensive sequencing of newborns will reveal numerous actionable uMDRs and precipitate substantial, and in some cases lifesaving, downstream medical care in newborns and their family members.
Topics: Humans; Infant, Newborn; Genetic Testing; Genome, Human; Neonatal Screening; Genomics; Exome Sequencing
PubMed: 37279760
DOI: 10.1016/j.ajhg.2023.05.007 -
Clinics in Laboratory Medicine Mar 2018The process of conducting pathology research in Africa can be challenging. But the rewards in terms of knowledge gained, quality of collaborations, and impact on... (Review)
Review
The process of conducting pathology research in Africa can be challenging. But the rewards in terms of knowledge gained, quality of collaborations, and impact on communities affected by infectious disease and cancer are great. This report reviews 3 different research efforts: fatal malaria in Malawi, mucosal immunity to HIV in South Africa, and cancer research in Uganda. What unifies them is the use of pathology-based approaches to answer vital questions, such as physiology, pathogenesis, predictors of clinical course, and diagnostic testing schemes.
Topics: Africa; Biomedical Research; Clinical Laboratory Services; Developing Countries; Humans; Pathology, Clinical
PubMed: 29412886
DOI: 10.1016/j.cll.2017.10.006