Time to diagnosis in rapid exome/genome sequencing in the clinical inpatient setting.

Exome and genome sequencing are clinically available, with many laboratories offering expedited testing (e.g., "rapid" and "ultra-rapid"). With the increase in uptake of expedited testing, there is a need for the development of inpatient protocols for best practices based on real-life data. A retrospective 2-year review (October 2019-November 2021) of the utilization of rapid exome and genome sequencing for inpatient cases at a tertiary care center using a utilization management tracking database with subsequent chart review was performed. Thirty-three expedited "rapid/priority" exome/genome tests were performed clinically. The average total turnaround time (TAT) was 17.88 days (5-43 days) with an average TAT of 13.97 days (3-41 days) for the performing laboratory. There were 5 positive diagnostic results (15.2%), 3 likely positive diagnostic results (9%), 2 noncontributory results (6%), and 26 nondiagnostic results (69.7%). Real-life data suggest that there is an approximately 3.91-day lag in getting samples to the performing laboratory. Although laboratories may advertise their expected TAT, a number of factors can potentially impact the actual time from test order placement to communication of the results for clinical use. Understanding the points of delay will enable the development of internal protocols and policies to improve time to diagnosis.

A modified TOP assay to detect per- and polyfluoroalkyl substances in aqueous film-forming foams (AFFF) and soil.

Total oxidisable precursor (TOP) assay can oxidise some per- and polyfluoroalkyl substances (PFASs) and their precursors, most of which cannot be quantitatively detected so far, and convert them to detectable PFASs, such as perfluoroalkyl acids (PFAAs). However, the conversion is constrained by the complexity of the target samples, including co-existent organics, unknown PFAS precursors, and background. In this study, the TOP assay is modified to increase the oxidation and conversion efficiency by changing the initial concentration of target sample, increasing oxidising doses, time, temperature, etc. The modified TOP assay is applied to test several aqueous film-forming foams (AFFF) and a PFAS-contaminated soil extract. The sum concentrations of the detectable PFASs are increased by up to ∼534× in the AFFF samples and ∼7× in the PFAS-contaminated soil extract. The detectable fluorotelomer sulfonate (FTS, such as 6:2/8:2 FTS) is accounted as an oxidation indicator to monitor the oxidation and conversion progress of the oxidisable PFASs precursors to the detectable PFASs. Overall, the modified TOP assay could be an appropriate method for identifying missing PFASs mass in complex matrices by detecting the PFASs precursors effectively.

Effects of source materials on desorption kinetics of carcinogenic PAHs from contaminated soils.

Research investigating the desorptive behaviour of PAHs from contaminated soils often overlooked the effects of source materials, especially coal tar and coal tar pitch and materials alike. In this study, a refined experimental approach was adopted to establish a simple-to-complex continuum of systems that allow the investigation of desorption kinetics of benzo(a)pyrene (BaP) and 3 other carcinogenic PAHs (cPAHs) over an incubation period of 48 d. By comparing the modelled desorption parameters, elucidation of the effects of PAH source materials on their desorptive behaviour was achieved. Desorption of cPAHs from coal tar and pitch was enhanced when they were added to soils, with rapidly desorbing fraction (Frap) of BaP increased from 0.68% for pitch to 1.10% and 2.66% for pitch treated soils, and from 2.57% for coal tar to 6.24% for coal tar treated soil G and 8.76% for coal tar treated sand (1 d). At 1 d, desorption of target cPAHs from solvent and source material spiked soils generally followed the order of solvent > coal tar > pitch. Increases in Frap of cPAHs were observed in coal tar-treated soils after 48 d soil incubation (0.33%-1.16% for soil M, p ≥ 0.05, 6.24%-9.21% for soil G, p < 0.05) and was attributed to the continuous migration of coal tar as a non-aqueous phase liquid (NAPL) into soil pore structures. Slow desorption was dominated by source materials, whereas the extents and rates of rapid desorption (Frap and krap) were more controlled by the quantity of soil organic matter (SOM), rather than quality of SOM (as in solvent-spiked soils). The results of this study challenged the role of PAH source materials as 'sinks' and led to the proposed roles of coal tar and pitch and source materials alike as 'reservoirs' with a risk-driven perspective.

Factors associated with the time to complete clinical exome sequencing in a pediatric patient population.

PURPOSE: Exome sequencing (ES) is becoming increasingly important for diagnosing rare genetic disorders. Patients and clinicians face several barriers when attempting to obtain ES. This study is aimed to describe factors associated with a longer time interval between provider recommendation of testing and sample collection for ES. METHODS: A retrospective chart review was conducted for insurance-authorized, completed pediatric ES in which initial requests were reviewed by Stanford's Genetic Testing Optimization Service between November 2018 and December 2019. Regression analysis was used to determine the association between the geocoded median household income and 3 different time point intervals defined as time to test, insurance decision, and scheduling/consent. RESULTS: Of the 281 charts reviewed, 115 cases were included in the final cohort. The average time from provider preauthorization request to sample collection took 104.4 days, and income was negatively correlated with the length of the insurance decision interval. CONCLUSION: Pediatric patients undergo a lengthy, uncertain process when attempting to obtain ES, some of which is associated with income. More research and clinician interventions are required to clarify specific socioeconomic factors that influence the ability to obtain timely ES and develop optimal protocols.

Abiotic factors controlling bioavailability and bioaccessibility of polycyclic aromatic hydrocarbons in soil: Putting together a bigger picture.

The bioavailability and bioaccessibility of polycyclic aromatic hydrocarbons (PAHs) in soil underpin the risk assessment of contaminated land with these contaminants. Despite a significant volume of research conducted in the past few decades, comprehensive understanding of the factors controlling the behaviour of soil PAHs and a set of descriptive soil parameters to explain variations in PAH bioavailability and bioaccessibility are still lacking. This review focuses on the role of source materials on bioavailability and bioaccessibility of soil PAHs, which is often overlooked, along with other abiotic factors including contaminant concentration and mixture, soil composition and properties, as well as environmental factors. It also takes into consideration the implications of different types of risk assessment (ecological and human health) on bioavailability and bioaccessibility of PAHs in soil. We recommend that future research should (1) account for the effects of source materials on bioavailability and bioaccessibility of soil PAHs; (2) adopt non-disruptive methods to analyse soil components controlling PAH sequestration; (3) integrate both natural organic matter (NOM) and xenobiotic organic matter (XOM) while evaluating the influences of soil organic matter (SOM) on the behaviour of PAHs; and (4) consider the dissimilar desorption scenarios in ecological risk assessment and human health risk assessment while assessing PAH bioavailability and bioaccessibility.

Promoting appropriate genetic testing: the impact of a combined test review and consultative service.

PURPOSE: Genetic test misorders can adversely affect patient care. However, little is known about the types of misorders and the overall impact of a utilization management (UM) program on curbing misorders. This study aimed to identify different types of misorders and analyze the impact of a combined test review and consultative service on reducing misorders over time. METHODS: Selected genetic tests were systematically reviewed between January and December 2015 at Stanford Health Care. Misorders were categorized into five types: clerical errors, redundant testing, better alternatives, controversial, and uncategorized. Moreover, consultations were offered to help clinicians with test selection. RESULTS: Of the 629 molecular test orders reviewed, 13% were classified as misorders, and 7% were modified or canceled. Controversial misorders constitute the most common type (42%); however, unlike the other misorder types, they were negligibly affected by test review. Simultaneously, 71 consults were received. With the introduction of the UM program, genetic test misorders went from 22% at baseline to 3% at the end of the year. CONCLUSION: Our results show that the combined approach of test review and consultative service effectively reduced misorders over time and suggest that a UM program focused on eliminating misorders can positively influence health-care providers' behaviors.Genet Med advance online publication 26 January 2017.

Genotype-phenotype analysis of 4q deletion syndrome: proposal of a critical region.

Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a ∼465 kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes.