Implementing Pharmacogenomics Testing: Single Center Experience at Arkansas Children's Hospital.
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ABSTRACT:
SUBMITTER: Gill PS
PROVIDER: S-EPMC8150685 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Our institution developed and continuously improved a Neurodevelopmental Reflex (NDR) algorithm to help physicians with genetic test ordering for neurodevelopmental disorders (NDDs). To assess its performance, we performed a retrospective study of 511 patients tested through NDR from 2018 to 2019. SNP Microarray identified pathogenic/likely pathogenic copy number variations in 27/511 cases (5.28%). Among the 484 patients tested for Fragile X FMR1 CGG repeats, a diagnosis (0.20%) was established for one male mosaic for a full mutation, a premutation, and a one-CGG allele. Within the 101 normocephalic female patients tested for MECP2, two patients were found to carry pathogenic variants (1.98%). This retrospective study suggested the NDR algorithm effectively established diagnoses for patients with NDDs with a yield of 5.87%.
| S-EPMC9556427 | biostudies-literature
Project description:Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder featuring chronic lymphadenopathy, splenomegaly, cytopenias, and increased lymphoma risk. Differentiating ALPS from immunodeficiencies with overlapping symptoms is challenging. This study evaluated the performance and the diagnostic yield of a 15-gene NGS panel for ALPS at Cincinnati Children's Hospital Medical Center. Samples from 802 patients submitted for ALPS NGS panel were studied between May 2014 and January 2023. A total of 62 patients (7.7%) had a definite diagnosis: 52/62 cases (84%) showed 37 unique pathogenic/likely pathogenic germline FAS variants supporting ALPS diagnosis (6.5%, 52/802). The ALPS diagnostic yield increased to 30% in patients who additionally fulfilled abnormal ALPS immunology findings criteria. 17/37 (46%) diagnostic FAS variants were novel variants reported for the first time in ALPS. 10/802 cases (1.2%) showed diagnostic findings in five genes (ADA2, CTLA4, KRAS, MAGT1, NRAS) which are related to autoimmune lymphoproliferative immunodeficiency (ALPID). Family studies enabled the reclassification of variants of unknown significance (VUS) and also the identification of at-risk family members of FAS-positive patients, which helped in the follow-up diagnosis and treatment. Alongside family studies, complete clinical phenotypes and abnormal ALPS immunology and Fas-mediated apoptosis results helped clarify uncertain genetic findings. This study describes the largest cohort of genetic testing for suspected ALPS in North America and highlights the effectiveness of the ALPS NGS panel in distinguishing ALPS from non-ALPS immunodeficiencies. More comprehensive assessment from exome or genome sequencing could be considered for undefined ALPS-U patients or non-ALPS immunodeficiencies after weighing cost, completeness, and timeliness of different genetic testing options.
| S-EPMC11282156 | biostudies-literature
Project description:Background and objectives: Organ shortage is considered to be a major limitation for increasing transplantation rates. Brain-dead donors (DBDs) are an important source of organs, but up to 50% of potential DBDs might not be identified. An active brain-dead donor search could potentially increase a deceased donor pool. The aim of this study was to evaluate the effectiveness of an active potential DBD identification program and to evaluate one year impact on the potential organ donor pool in Lithuania's biggest medical institution. Materials and Methods: An organ donor coordinator service was established and active DBD search strategy was implemented in the hospital of LSMU Kauno Klinikos, and retrospective data analysis was performed between December 2016 and December 2017. Collected data was compared to the available data of the previous year in the same center and to the donation dynamics of the whole country. Results: A total of 6734 patients were treated in all intensive care units (ICU), and 234 (3.5%) of them were identified as possible donors. No increase in potential donor's number was observed in study year (n = 34) compared to remote year (n = 37). No significant difference in potential donor's demographic data, cause of death, family refusals and medical contraindication rates. Cerebral angiography (CA) repeated in 20% of potential donors in order to confirm brain death diagnosis. More potential donors for whom CA was repeated had decompressive craniectomy done (66.7% vs. 33.3%, p = 0.018). Decompressive craniectomy statistically significantly increases the rate of repeated CA (OR 12.7; 95% CI, 1.42-113.37; p = 0.023). Active search strategy increased length of hospital stay of potential donors comparing to previous year (3.97 ± 4.73 vs. 2.51 ± 2.63, p = 0.003). An optimal time of the first four days of hospitalization to identify a potential donor was observed during our study (OR 10.42; 95% CI, 4.29-25.34; p = 0.001). Conclusions: We were not able to demonstrate active donor identification strategy superiority over the passive strategy during a short one year period; nevertheless, valuable knowledge was gained in brain death diagnostics, new terminology was implemented, and the stability of actual donor numbers was observed in the experimental donor center in the light of decreasing national results. Long-term strategy is required to achieve sustainable results in organ donation.
| S-EPMC7466291 | biostudies-literature
Project description:BackgroundInborn errors of immunity (IEI) are a group of heterogeneous disorders with geographic and ethnic diversities. Although IEI are common in Egypt, genetic diagnosis is limited due to financial restrictions. This study aims to characterize the genetic spectrum of IEI patients in Egypt and highlights the adaptation of the molecular diagnostic methods to a resource-limited setting.MethodsGenetic material from 504 patients was studied, and proper diagnosis was achieved in 282 patients from 246 families. Mutational analysis was done by Sanger sequencing, next-generation sequencing (NGS) targeting customized genes panels, and whole-exome sequencing (WES) according to the patients' phenotypes and availability of genetic testing.ResultsA total of 194 variants involving 72 different genes were detected with RAG1/2 genes being the most encountered followed by DOCK8, CYBA, LRBA, NCF1, and JAK3. Autosomal recessive (AR) inheritance was detected in 233/282 patients (82.6%), X-linked (XL) recessive inheritance in 32/282 patients (11.3%), and autosomal dominant (AD) inheritance in 18/282 patients (6.4%), reflecting the impact of consanguineous marriages on the prevalence of different modes of inheritance and the distribution of the various IEI disorders.ConclusionThe study showed that a combination of Sanger sequencing in selected patients associated with targeted NGS or WES in other patients is an effective diagnostic strategy for IEI diagnosis in countries with limited diagnostic resources. Molecular testing can be used to validate other nonexpensive laboratory techniques that help to reach definitive diagnosis and help in genetic counseling and taking proper therapeutic decisions including stem cell transplantation or gene therapy.
| S-EPMC9402523 | biostudies-literature
Project description:Due to its rarity, male breast cancer remains a poorly characterized disease. The present study obtained retrospective clinicopathological data, treatment patterns and outcomes for all male patients diagnosed with breast cancer in the Oncology Department, Faculty Hospital Tren?ín (Tren?ín, Slovakia) over the last 20 years from January 1995 to December 2015. A total of 21 patients with male breast cancer were analyzed, with a median patient age of 65.6 years. Two patients were diagnosed with lobular invasive cancer; all others were diagnosed with cancer of a ductal origin. One patient presented with metastatic disease in the pleural cavity. The primary tumors in 8 patients were staged as pT1, whilst 6 patients were staged as pT2 and 7 as pT4. Axillary lymph node involvement was present in 11 patients (52%) and 15 patients were hormone receptor-positive (83%). All but 1 patient underwent mastectomy and surgical staging of the axilla. Adjuvant chemotherapy, radiotherapy and hormone treatment was administered in the same manner as breast cancer treatment in female patients. The median follow-up time was 4.5 years. The 5- and 10-year overall survival rates were 87 and 74%, respectively, and the estimated median disease-free survival for the same population was 9.5 years (95% confidence interval, 6.2-14.6). The survival rates reported in the present retrospective study are comparable with previously published studies. In addition, the current study reported predominant hormone-positive characteristics and rare expression of human epidermal growth factor receptor 2. However, further multi-institutional trials are required to allow for informed treatment decisions in this uncommon disease.
| S-EPMC4950425 | biostudies-other
Project description:Intensive care units (ICU) rely on multiple technical resources with extensive use of different medical devices, such as ventilators, vital sign monitors, infusion, and injection pumps. This study explored how ICU nurses approach adverse events related to medical devices in a single tertiary center and identify their level of awareness of the national reporting system for adverse events related to medical devices beside their source for risk information updates. Totally, 297 nurses working in the ICU at King Saud University Medical City completed a survey on medical devices and adverse events reporting and 198 reported experiencing an adverse event related to equipment failure. However, 195 nurses were unaware of an official national reporting system for reporting such events. It is important to develop a framework of safe operation of medical devices based on international standards. This reporting system should include the national patients' safety authorities, and should be anonymous, confidential, and non-punitive.
| S-EPMC6812847 | biostudies-literature
Project description:There is limited evidence to support pharmacogenetic (PGx) testing in children. We conducted a retrospective review of PGx testing among 452 patients at an academic children's hospital to determine the potential utility of PGx in diseases of childhood and to identify targets for future pediatric pharmacogenetic research. An actionable gene-drug pair associated with the 28 genes tested (Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B, Pharmacogenomics Knowledge Base (PharmGKB) level 1A or B, or US Food and Drug Administration (FDA) recommendation and a PharmGKB level) was present in 98.7% of patients. We identified 203 actionable gene-drug-diagnosis groups based on the indications for each actionable drug listed in Lexicomp. Among patients with an actionable gene-drug-diagnosis group, 49.3% had a diagnosis where the drug was a therapeutic option and PGx could be used to guide treatment selection. Among patients with an associated diagnosis, 30.9% had a prescription for the actionable drug allowing PGx guided dosing. Three genes (CYP2C19, CYP2D6, and CYP3A5) accounted for all the gene-drug-diagnosis groups with matching diagnoses and prescriptions. The most common gene-drug-diagnosis groups with matching diagnoses and prescriptions were CYP2C19-citalopram-escitalopram-depression 3.3% of patients tested; CYP2C19-dexlansoprazole-gastritis-esophagitis 3.1%; CYP2C19-omeprazole-gastritis-esophagitis 2.4%; CYP2D6-atomoxetine-attention deficit hyperactivity disorder 2.2%; and CYP2C19-citalopram-escitalopram-obsessive-compulsive disorder 1.5%. PGx could be used to guide selection of current treatment options or medication dosing in almost half (48.7%) of pediatric patients tested. Mood disorders and gastritis/esophagitis are promising targets for future study of PGx testing because of the high prevalence of these diagnoses and associated actionable gene-drug pairs in the pediatric population.
| S-EPMC7877836 | biostudies-literature
Project description:BackgroundGenetic testing for cancer predisposition is recommended to women with breast cancer who meet the criteria for such testing. After the FDA approvals of the poly ADP ribose polymerase (PARP) inhibitors, olaparib and talazoparib, for treatment of metastatic breast cancer, carrying germline mutations in BRCA1 and BRCA2 genes, the genetic testing result has become critical in their care. With the recent FDA approval of alpelisib for the treatment of PIK3CA-mutated hormone-receptor positive metastatic breast cancer, tumor molecular profiling to identify somatic mutations and potential molecularly targeted agents is increasingly utilized in the treatment of advanced breast cancer.AimCombining germline and somatic sequencing (paired testing) offers an advantage over a single technique approach. Our study evaluates the role of paired testing on the management of breast cancer patients.Methods and resultsForty-three breast cancer patients treated at Rush University Medical Center underwent paired germline and somatic variant testing in 2015 to 2017. A retrospective chart review was conducted with the analysis of demographic, clinical, and genomic data. Three actionable germline variants were found in the CHEK2 (2) and ATM (1) genes. 95% of tumors had somatic mutations. Seventy-seven percent of tumors had genomic alterations targetable with agents approved for breast cancer and 88% had molecular targets for agents approved for other cancers. Clinical examples of such use are described and potential future directions of tumor and paired testing are discussed.ConclusionsGermline variants were present in a relatively small patient group not routinely tested for inherited alterations. Potentially targetable somatic alterations were identified in the majority of breast cancers. Paired testing is a feasible and efficient approach that delivers valuable information for the care of breast cancer patients and eliminates serial testing.
| S-EPMC7941483 | biostudies-literature
Project description: Not available
| S-EPMC11372899 | biostudies-literature
Project description:IntroductionWe used the plan-do-study-act (PDSA) framework to develop and implement an evidence-based clinical practice guideline (CPG) within an urban, tertiary children's referral center.MethodsWe developed an evidence-based CPG for appendicitis using iterative PDSA cycles. Similar CPGs from other centers were reviewed and modified for local implementation. Adjuncts included guideline-specific order sets and operative notes in the electronic medical record system. Outcomes included length of stay (LOS), 30-day readmissions, hospital costs, and patient and family experience (PFE) scores. Our team tracked outcome, process, and balancing measures using Statistical Process Charts. Outcome measures were compared over 2 fiscal quarters preimplementation and 3 fiscal quarters postimplementation, using interrupted time series, student t test, and chi-square tests when appropriate.ResultsLOS for simple (uncomplicated) appendicitis decreased to 0.87 days (interquartile range [IQR] 0.87-0.94 days) from 1.1 days (IQR 0.97-1.42 days). LOS for complicated appendicitis decreased to 4.96 days (IQR 4.95-6.15) from 5.58 days (IQR 5.16-6.09). This reduction equated to an average cost-savings of $1,122/patient. Thirty-day readmission rates have remained unchanged. PFE scores increased across all categories and have remained higher than national benchmarks.ConclusionDevelopment and Implementation of a CPG for pediatric appendicitis using the PDSA framework adds value to care provided within a large tertiary center.
| S-EPMC8322485 | biostudies-literature