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The work : searching for a life that matters
The Work is the story of how one young man traced a path through the world to find his life's purpose. Wes Moore graduated from a difficult childhood in the Bronx and Baltimore to an adult life that would find him at some of the most critical moments in our recent history: as a combat officer in Afghanistan; a White House fellow in a time of wars abroad and disasters at home; and a Wall Street banker during the financial crisis. In this insightful book, Moore shares the lessons he learned from people he met along the way--from the brave Afghan translator who taught him to find his fight, to the resilient young students in Katrina-ravaged Mississippi who showed him the true meaning of grit, to his late grandfather, who taught him to find grace in service.--Back cover.
Book
Blacklisting variants common in private cohorts but not in public databases optimizes human exome analysis
Computational analyses of human patient exomes aim to filter out as many nonpathogenic genetic variants (NPVs) as possible, without removing the true disease-causing mutations. This involves comparing the patient’s exome with public databases to remove reported variants inconsistent with disease prevalence, mode of inheritance, or clinical penetrance. However, variants frequent in a given exome cohort, but absent or rare in public databases, have also been reported and treated as NPVs, without rigorous exploration. We report the generation of a blacklist of variants frequent within an in-house cohort of 3,104 exomes. This blacklist did not remove known pathogenic mutations from the exomes of 129 patients and decreased the number of NPVs remaining in the 3,104 individual exomes by a median of 62%. We validated this approach by testing three other independent cohorts of 400, 902, and 3,869 exomes. The blacklist generated from any given cohort removed a substantial proportion of NPVs (11–65%). We analyzed the blacklisted variants computationally and experimentally. Most of the blacklisted variants corresponded to false signals generated by incomplete reference genome assembly, location in low-complexity regions, bioinformatic misprocessing, or limitations inherent to cohort-specific private alleles (e.g., due to sequencing kits, and genetic ancestries). Finally, we provide our precalculated blacklists, together with ReFiNE, a program for generating customized blacklists from any medium-sized or large in-house cohort of exome (or other next-generation sequencing) data via a user-friendly public web server. This work demonstrates the power of extracting variant blacklists from private databases as a specific in-house but broadly applicable tool for optimizing exome analysis.
Journal Article
The museum of Wes Anderson : his movies and the works that inspired them
\"Welcome to the Wes Anderson museum - a place packed with illustrations, ephemera, trivia, and insightful commentary, and as whimsical and visually arresting as the cult director's films themselves. This museum in book form takes readers deep into the world of Wes Anderson. Bursting with an exhaustive and eclectic collection of film stills, accessories, clothes, souvenirs, books, and delightfully bizarre ephemera, this immersive treasury offers extraordinary insight into Wes Anderson's literary, musical, and cinematic influences, which range from Indian cinema, French pop music, Italian speed car racing, to The New Yorker magazine and the work of J. D. Salinger. Among the museum's artifacts are a recipe for a ham sandwich from The French Dispatch's Le Sans Blague café; the history of Tang - the drink of choice for the campers in Moonrise Kingdom; and the secret of L'Air de Panache, the cologne worn by the concierge of the Grand Budapest Hotel. Readers will discover Anderson's connections to the balalaika, The Beatles, and Benjamin Britten, and they'll discover how the filmmaker was inspired by the works of Hal Ashby, Satyajit Ray, Orson Welles, Mike Nichols, and Francis Ford Coppola. Perfect for dipping into and filled with information that will surprise even the most diehard Wes Anderson fan, this technicolor treasury is as profoundly entertaining as it is authoritative\"--Publisher's description.
BOOK
Clinical whole-exome sequencing: are we there yet?
Background:
Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.
Methods:
We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers.
Results:
A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory’s quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost.
Conclusion:
Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.
Genet Med
16
9, 717–719.
Journal Article
A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders
To prospectively evaluate the diagnostic and clinical utility of singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic disease.
Singleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center. This occurred in parallel with standard investigations, including single- or multigene panel sequencing when clinically indicated. The diagnosis rate, clinical utility, and impact on management of singleton WES were evaluated.
Of 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group. Clinical management changed following exome diagnosis in 15 of 46 diagnosed participants (32.6%). Twelve relatives received a genetic diagnosis following cascade testing, and 28 couples were identified as being at high risk of recurrence in future pregnancies.
This prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier sequencing test for infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner.
Genet Med18 11, 1090–1096.
Journal Article
Wes Craven : the man and his nightmares
A portrait of cult film director Wes Craven's life and career in film Draws on the author's new interviews with Craven, including little-known details about the director's life.
Book
Somatic mutational landscape in von Hippel–Lindau familial hemangioblastoma
Von Hippel–Lindau disease (vHL) predisposes to tumor development, mainly clear cell renal carcinoma and hemangioblastoma. The underlying cause is germline variants in the VHL gene, with tumorigenesis thought to require additional somatic ‘second‐hit’ events that most commonly include loss of 3p. However, the precise mechanisms of vHL‐related tumor development remain incompletely understood. Genomic investigations of familial hemangioblastoma may help elucidate the early steps of tumorigenesis and contribute to improved disease prediction, biomarker discovery, and therapeutic strategies. We performed whole exome sequencing on 22 familial hemangioblastomas from 7 patients representing 5 unrelated families, and with 4 different causative VHL genotypes. The tumors exhibited low overall mutational burden but showed frequent loss of heterozygosity on chromosome 3 or 3p and single nucleotide variants in the VHL region. Variants were significantly enriched in genes associated with GABAergic and serotonergic neuronal cell types, as well as in pathways regulating cell cycle and neurogenesis. These findings suggest that, in addition to VHL loss, dysregulation of neuronal differentiation programs and cell cycle control may play important roles in hemangioblastoma tumorigenesis.
Journal Article