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Purpose: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS., Methods: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC ( BRCA1 and BRCA1 ) and LS ( MLH1 , MSH2 , MSH6 , PMS2 , and EPCAM ). Chart review was performed to collect demographics and personal and family cancer history., Results: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1 , 42.8% BRCA2 ) and 163 with LS (12.3% MSH6 , 8.8% PMS2 , 4.5% MLH1 , 3.8% MSH2 , and 0.2% EPCAM ). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028)., Conclusion: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.

Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genomic databases to enable rapid review of genomic findings. We tested RENEW in an unselected cohort of 1066 undiagnosed cases with a broad spectrum of phenotypes from the Mayo Clinic Center for Individualized Medicine using new information in ClinVar, HGMD and OMIM between the date of previous analysis/testing and April of 2022. 5741 variants prioritized by RENEW were rapidly reviewed by variant interpretation specialists. Mean analysis time was approximately 20 s per variant (32 h total time). Reviewed cases were classified as: 879 (93.0%) undiagnosed, 63 (6.6%) putatively diagnosed, and 4 (0.4%) definitively diagnosed. New strategies are needed to enable efficient review of genomic findings in unsolved cases. We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education., Methods: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers., Results: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results., Conclusion: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities., (© 2023. The Author(s).)

Purpose: The Mayo-Baylor RIGHT 10K Study enabled preemptive, sequence-based pharmacogenomics (PGx)-driven drug prescribing practices in routine clinical care within a large cohort. We also generated the tools and resources necessary for clinical PGx implementation and identified challenges that need to be overcome. Furthermore, we measured the frequency of both common genetic variation for which clinical guidelines already exist and rare variation that could be detected by DNA sequencing, rather than genotyping., Methods: Targeted oligonucleotide-capture sequencing of 77 pharmacogenes was performed using DNA from 10,077 consented Mayo Clinic Biobank volunteers. The resulting predicted drug response-related phenotypes for 13 genes, including CYP2D6 and HLA, affecting 21 drug-gene pairs, were deposited preemptively in the Mayo electronic health record., Results: For the 13 pharmacogenes of interest, the genomes of 79% of participants carried clinically actionable variants in 3 or more genes, and DNA sequencing identified an average of 3.3 additional conservatively predicted deleterious variants that would not have been evident using genotyping., Conclusion: Implementation of preemptive rather than reactive and sequence-based rather than genotype-based PGx prescribing revealed nearly universal patient applicability and required integrated institution-wide resources to fully realize individualized drug therapy and to show more efficient use of health care resources., Competing Interests: Conflict of Interest Liewei Wang, John Logan Black III, and Richard M. Weinshilboum are cofounders of and stockholders in OneOme, LLC, which was used only to return results to the study participants. Additionally, John Logan Black III and Mayo Clinic Ventures have applied for a patent on the CNVAR software cited in this study as well as the methodology upon which the software is based. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: The Pharmacogenomics (PGx) Profile Service was a proof-of-concept project to implement PGx in patient care at Mayo Clinic., Methods: Eighty-two healthy individuals aged 18 and older underwent genotyping of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, HLA-B*58:01, and VKORC1. A PGx pharmacist was involved in ordering, meeting with patients, interpreting, reviewing, and documenting results., Results: Ninety three percent were CYP1A2 rapid metabolizers, 92% CYP3A4 normal metabolizers, and 88% CYP3A5 poor metabolizers; phenotype frequencies for CYP2C19 and CYP2D6 varied. Seventy-three percent had normal functioning SLCO1B1 transporter, 4% carried the HLA-B*58:01 risk variant, and 35% carried VKORC1 and CYP2C9 variants that increased warfarin sensitivity., Conclusion: Pre-emptive PGx testing offered medication improvement opportunity in 56% of participants for commonly used medications. A collaborative approach involving a PGx pharmacist integrated within a clinical practice with regards to utility of PGx results allowed for implementation of the PGx Profile Service., Key Points: The Mayo Clinic PGx (PGx) Profile Service was a proof-of-concept project to utilize PGx testing as another clinical tool to enhance medication selection and decrease serious adverse reactions or medication failures. Over one-half of participants in the pilot using the PGx Profile Service were predicted to benefit from pre-emptive PGx testing to guide pharmacotherapy. PGx pharmacists played a crucial role in the PGx Profile Service by educating participants, identifying medication-gene interactions, and providing evidence-based (CPIC and DPWG) PGx recommendations for past, current, and future medication us., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To assess the presence of clinically actionable results and other genetic findings in an otherwise healthy population of adults seen in a medical practice setting and offered "predictive" genomic testing., Patients and Methods: In 2014, a predictive genomics clinic for generally healthy adults was launched through the Mayo Clinic Executive Health Program. Self-identified interested patients met with a genomic nurse and genetic counselor for pretest advice and education. Two genome sequencing platforms and one gene panel-based health screen were offered. Posttest genetic counseling was available for patients who elected testing. From March 1, 2014, through June 1, 2019, 1281 patients were seen and 301 (23.5%) chose testing. Uptake rates increased to 36.3% [70 of 193]) in 2019 from 11.8% [2 of 17] in 2014. Clinically actionable results and genetic findings were analyzed using descriptive statistics., Results: Clinically actionable results were detected in 11.6% of patients (35 of 301), and of those, 51.7% (15 of 29) with a cancer or cardiovascular result = did not have a personal or family history concerning for a hereditary disorder. The most common actionable results were in the BCHE, BRCA2, CHEK2, LDLR, MUTYH, and MYH7 genes. A carrier of at least one recessive condition was found in 53.8% of patients (162 of 301). At least one variant associated with multifactorial disease was found in 44.5% (134 of 301) (eg, 25 patients were heterozygous for the F5 factor V Leiden variant associated with thrombophilia risk)., Conclusion: Our predictive screening revealed that 11.6% of individuals will test positive for a clinically actionable, likely pathogenic/pathogenic variant. This finding suggests that wider knowledge and adoption of predictive genomic services could be beneficial in medical practice, although additional studies are needed., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing., Methods: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses., Results: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient., Conclusion: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

Objective: To demonstrate experience and feasibility of a precision medicine approach for patients with unexplained cytopenias, defined as low blood counts in one or more cell lineages, persistent for 6 months or longer, in the absence of known nutritional, autoimmune, infectious, toxic, and neoplastic (secondary) causes., Patients and Methods: Patients were evaluated in our clinic between November 8, 2016, and January 12, 2018. After a thorough evaluation of known causes, family history, and appropriate clinical assays, genomic evaluation was performed in a stepwise manner, through Sanger, targeted, and/or whole-exome sequencing. Variants were analyzed and discussed in a genomics tumor board attended by clinicians, bioinformaticians, and molecular biologists., Results: Sixty-eight patients were evaluated in our clinic. After genomic interrogation, they were classified into inherited bone marrow failure syndromes (IBMFS) (n=24, 35%), cytopenias without a known clinical syndrome which included idiopathic and clonal cytopenias of undetermined significance (CCUS) (n=30, 44%), and patients who did not fit into the above two categories ("others," n=14, 21%). A significant family history was found in only 17 (25%) patients (9 IBMFS, 2 CCUS, and 6 others), whereas gene variants were found in 43 (63%) patients (34 [79%] pathogenic including 12 IBMFS, 17 CCUS, and 5 others]. Genomic assessment resulted in a change in clinical management in 17 (25%) patients, as evidenced by changes in decisions with regards to therapeutic interventions (n=8, 47%), donor choice (n=6, 35%), and/or choice of conditioning regimen for hematopoietic stem cell transplantation (n=8, 47%)., Conclusion: We show clinical utility of a real-world algorithmic precision medicine approach for unexplained cytopenias., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of the present study was to document the efficacy of electropalatography (EPG) for the treatment of rhotic errors in school-age children. Despite a growing body of literature using EPG for the treatment of speech sound errors, there is little systematic evidence about the relative efficacy of EPG for rhotic errors., Method: Participants were 5 English-speaking children aged 6;10 to 9;10, who produced /r/ at the word level with < 30% accuracy but otherwise showed typical speech, language, and hearing abilities. Therapy was delivered in twice-weekly 30-min sessions for 8 weeks., Results: Four out of 5 participants were successful in achieving perceptually and acoustically accurate /r/ productions during within-treatment trials. Two participants demonstrated generalization of /r/ productions to nontreated targets, per blinded listener ratings., Conclusions: The present findings support the hypothesis that EPG can improve production accuracy in some children with rhotic errors. However, the utility of EPG is likely to remain variable across individuals. For rhotics, EPG training emphasizes one possible tongue configuration consistent with accurate rhotic production (lateral tongue contact). Although some speakers respond well to this cue, the narrow focus may limit lingual exploration of other acceptable tongue shapes known to facilitate rhotic productions.

Purpose: Recent research suggests that visual-acoustic biofeedback can be an effective treatment for residual speech errors, but adoption remains limited due to barriers including high cost and lack of familiarity with the technology. This case study reports results from the first participant to complete a course of visual-acoustic biofeedback using a not-for-profit iOS app, Speech Therapist's App for /r/ Treatment., Method: App-based biofeedback treatment for rhotic misarticulation was provided in weekly 30-min sessions for 20 weeks. Within-treatment progress was documented using clinician perceptual ratings and acoustic measures. Generalization gains were assessed using acoustic measures of word probes elicited during baseline, treatment, and maintenance sessions., Results: Both clinician ratings and acoustic measures indicated that the participant significantly improved her rhotic production accuracy in trials elicited during treatment sessions. However, these gains did not transfer to generalization probes., Conclusions: This study provides a proof-of-concept demonstration that app-based biofeedback is a viable alternative to costlier dedicated systems. Generalization of gains to contexts without biofeedback remains a challenge that requires further study. App-delivered biofeedback could enable clinician-research partnerships that would strengthen the evidence base while providing enhanced treatment for children with residual rhotic errors., Supplemental Material: https://doi.org/10.23641/asha.5116318.

Purpose: Single-case experimental designs are widely used to study interventions for communication disorders. Traditionally, single-case experiments follow a response-guided approach, where design decisions during the study are based on participants' observed patterns of behavior. However, this approach has been criticized for its high rate of Type I error. In masked visual analysis (MVA), response-guided decisions are made by a researcher who is blinded to participants' identities and treatment assignments. MVA also makes it possible to conduct a hypothesis test assessing the significance of treatment effects., Method: This tutorial describes the principles of MVA, including both how experiments can be set up and how results can be used for hypothesis testing. We then report a case study showing how MVA was deployed in a multiple-baseline across-subjects study investigating treatment for residual errors affecting rhotics. Strengths and weaknesses of MVA are discussed., Conclusions: Given their important role in the evidence base that informs clinical decision making, it is critical for single-case experimental studies to be conducted in a way that allows researchers to draw valid inferences. As a method that can increase the rigor of single-case studies while preserving the benefits of a response-guided approach, MVA warrants expanded attention from researchers in communication disorders.

Background: We characterized the pharmacogenomics (PGx) results received by diagnostic odyssey patients as secondary findings during clinical whole exome sequencing (WES) testing as a part of their care in Mayo Clinic's Individualized Medicine Clinic to determine the potential benefits and limitations to this cohort., Methods: WES results on 94 patients included a subset of PGx variants in CYP2C19 , CYP2C9 , and VKORC1 if identified in the patient. Demographic, phenotypic, and medication usage information was abstracted from patient medical data. A pharmacist interpreted the PGx results in the context of the patients' current medication use and made therapeutic recommendations., Results: The majority was young with a median age of 10 years old, had neurological involvement in the disease presentation (71%), and was currently taking medications (90%). Of the 94 PGx-evaluated patients, 91% had at least one variant allele reported and 20% had potential immediate implications on current medication use., Conclusion: Due to the disease complexity and medication needs of diagnostic odyssey patients, there may be immediate benefit obtained from early life PGx testing for many and most will likely find benefit in the future. These results require conscientious interpretation and management to be actionable for all prescribing physicians throughout the lifetime of the patient.

Purpose: Genomic testing has increased the quantity of information available to oncologists. Unfortunately, many identified sequence alterations are variants of unknown significance (VUSs), which thus limit the clinician's ability to use these findings to inform treatment. We applied a combination of in silico prediction and molecular modeling tools and laboratory techniques to rapidly define actionable VUSs., Materials and Methods: Exome sequencing was conducted on 308 tumors from various origins. Most single nucleotide alterations within gene coding regions were VUSs. These VUSs were filtered to identify a subset of therapeutically targetable genes that were predicted with in silico tools to be altered in function by their variant sequence. A subset of receptor tyrosine kinase VUSs was characterized by laboratory comparison of each VUS versus its wild-type counterpart in terms of expression and signaling activity., Results: The study identified 4,327 point mutations of which 3,833 were VUSs. Filtering for mutations in genes that were therapeutically targetable and predicted to affect protein function reduced these to 522VUSs of interest, including a large number of kinases. Ten receptortyrosine kinase VUSs were selected to explore in the laboratory. Of these, seven were found to be functionally altered. Three VUSs (FGFR2 F276C, FGFR4 R78H, and KDR G539R) showed increased basal or ligand-stimulated ERK phosphorylation compared with their wild-type counterparts, which suggests that they support transformation. Treatment of a patient who carried FGFR2 F276C with an FGFR inhibitor resulted in significant and sustained tumor response with clinical benefit., Conclusion: The findings demonstrate the feasibility of rapid identification of the biologic relevance of somatic mutations, which thus advances clinicians' ability to make informed treatment decisions., Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relation-ships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc. Jan B. Egan No relationship to disclose David L. Marks Stock and Other Ownership Interests: WebMD, Cardinal Health (I), Prothena (I), Perrigo (I) Tara L. Hogenson No relationship to disclose Anne M. Vrabel No relationship to disclose Ashley N. Sigafoos No relationship to disclose Ezequiel J. Tolosa No relationship to disclose Ryan M. Carr No relationship to disclose Stephanie L. Safgren No relationship to disclose Elisa Enriquez Hesles No relationship to disclose Luciana L. Almada No relationship to disclose Paola A. Romecin-Duran No relationship to disclose Eriko Iguchi No relationship to disclose Aryan Ala’Aldeen No relationship to disclose Jean-Pierre A. Kocher No relationship to disclose Gavin R. Oliver No relationship to disclose Naresh Prodduturi No relationship to disclose David W. Mead No relationship to disclose Asif Hossain No relationship to disclose Norine E. Huneke No relationship to disclose Colleen M. Tagtow No relationship to disclose Sikander Ailawadhi Consulting or Advisory Role: Amgen, Takeda Pharmaceuticals, Novartis Research Funding: Pharmacyclics (Inst) Travel, Accommodations, Expenses: Amgen, Takeda Pharmaceuticals, Novartis Stephen M. Ansell Honoraria: WebMD, Research To Practice Research Funding: Bristol-Myers Squibb (Inst), Celldex Therapeutics (Inst), Seattle Genetics (Inst), Merck (Inst), Affimed (Inst), Trillium Therapeutics (Inst) Michaela S. Banck No relationship to disclose Alan H. BryceNo relationship to disclose Estrella M. Carballido No relationship to disclose Asher A. Chanan-Khan No relationship to disclose Kelly K. Curtis Employment: INC Research Stock and Other Ownership Interests: INC Research Travel, Accommodations, Expenses: INC Research Ernesto ResnikNo relationship to disclose Chelsea D. Gawryletz No relationship to disclose Ronald S. Go Speakers’ Bureau: OnLive, Takeda Pharmaceuticals Thorvardur R. Halfdanarson Consulting or Advisory Role: Lexicon (Inst), Ipsen (Inst), Merrimack (Inst) Research Funding: Esanex (Inst), Ipsen (Inst), Boston Biomedical (Inst) Thai H. Ho No relationship to disclose Richard W. Joseph Consulting or Advisory Role: Bristol-Myers Squibb, Nektar, Genoptix, Eisai, Bristol-Myers Squibb Research Funding: Merck, Bristol-Meyers Squibb, Roche (Inst), Genentech (Inst), X4P Pharmaceuticals (Inst), Amgen (Inst) Prashant Kapoor Consulting or Advisory Role: Sanofi (Inst) Research Funding: Amgen (Inst), Takeda Pharmaceuticals (Inst) Aaron S. Mansfield Consulting or Advisory Role: TrovaGene (Inst), Genentech (Inst), Bristol-Myers Squibb (Inst) Travel, Accommodations, Expenses: Bristol-Myers Squibb Nathalie Meurice No relationship to disclose Amulya A. Nageswara Rao No relationship to disclose Grzegorz S. Nowakowski Consulting or Advisory Role: Celgene (Inst), MorphoSys (Inst), Genentech (Inst) Research Funding: Celgene (Inst) Animesh Pardanani No relationship to disclose Sameer A. Parikh Research Funding: Pharmacyclics (Inst) John C. Cheville No relationship to disclose Andrew L. Feldman Consulting or Advisory Role: Infinity Pharmaceuticals Patents, Royalties, Other Intellectual Property: Inventor of technology for which the Mayo Clinic holds an unlicensed patent or has submitted a patent application (Inst) Ramesh K. Ramanathan Honoraria: Taiho Pharmaceutical, Cerulean Pharma, Pharmacyclics, Insys Therapeutics, Novocure Consulting or Advisory Role: Cerulean Pharma, Novocure, INSYS Therapeutics, Pharmacyclics Research Funding: AbbVie (Inst), Celgene (Inst), Merck (Inst), Schering Plough (Inst), Merrimack (Inst), Boston Biomedical (Inst), BERG (Inst), Superlab Far East (Inst) Steven I. Robinson Travel, Accommodations, Expenses: Tricon Pharmaceuticals Raoul Tibes Research Funding: Novartis (Inst), Merck (Inst), Seattle Genetics (Inst), Boehringer Ingelheim (Inst), Astellas Pharma (Inst), Astex Pharmaceuticals (Inst)Heidi D. Finnes Jennifer B. McCormick No relationship to disclose Robert R. McWilliams Consulting or Advisory Role: Merrimack (Inst) Research Funding: PRISM BioLab (Inst), Genentech (Inst), Novartis (Inst), NewLink Genetics (Inst), Eli Lilly (Inst), Aduro Biotech (Inst), Pfizer (Inst), Sanofi (Inst) Travel, Accommodations, Expenses: AstraZeneca Aminah Jatoi Research Funding: Entera Health, Boston Biologics Mrinal M. Patnaik No relationship to disclose Alvin C. Silva No relationship to disclose Eric D. Wieben Patents, Royalties, Other Intellectual Property: Champions Oncology–licensed IP-targeted therapy with abiraterone acetate ($0 received), WuXi AppTec–licensed IP-breast cancer xenografts ($12,737 to Mayo Clinic; Inst), Affymetrix-licensed IP on several variants in drug processing enzymes ($0 in past 2 years), Life Technologies–licensed IP on several variants in drug processing enzymes ($0 in past 2 years) Tammy M. McAllister No relationship to disclose Kandelaria M. Rumilla No relationship to disclose Sarah E. Kerr Research Funding: Abbott Molecular Konstantinos N. Lazaridis No relationship to disclose Gianrico Farrugia No relationship to disclose A. Keith Stewart Consulting or Advisory Role: Celgene, Bristol-Myers Squibb, Janssen Pharmaceuticals, Roche, Amgen Karl J. Clark Patents, Royalties, Other Intellectual Property: Inventor on patents associated with the Sleeping Beauty transposon system Eileen J. Kennedy Patents, Royalties, Other Intellectual Property: Patent on unrelated work (US patent 9,458,189) for “ligation of stapled polypeptides” issued October 4, 2016 Eric W. Klee Patents, Royalties, Other Intellectual Property: Royalties on software development Mitesh J. Borad Stock and Other Ownership Interests: GlaxoSmithKline, Gilead Sciences Consulting or Advisory Role: G1 Therapeutics, TD2, Fujifilm (Inst), Agios (Inst), INSYS Therapeutics (Inst), Novartis (Inst), ArQule (Inst), Celegene (Inst), Inspyr Therapeutics, Halozyme Therapeutics (Inst) Research Funding: Boston Biomedical (Inst), miRNA Therapeutics (Inst), Senhwa Biosciences (Inst), Medimmune (Inst), Bioline (Inst), Agios (Inst), Halozyme Therapeutics (Inst), Celgene (Inst), Threshold Pharmaceuticals (Inst), Toray (Inst), Dicerna Pharmaceuticals (Inst), Sillajen (Inst), Eisai (Inst), Taiho Pharmaceuticals (Inst), EMD Serono (Inst), Isis Pharmaceuticals (Inst), Incyte (Inst), Sun BioPharma (Inst), ARIAD Pharmaceuticals (Inst), ImClone Systems (Inst) Travel, Accommodations, Expenses: ArQule, Celgene, AstraZeneca Martin E. Fernandez-Zapico No relationship to disclose

In this article, we describe how Phon, an open-source software program for the transcription and analysis of phonological data, can be applied to facilitate clinical phonological analyses. We begin with a summary of the types of analyses that are frequently used in the assessment and management of speech sound disorders. We then discuss challenges inherent to the transcription and analysis of clinical phonological data. For each challenge, we discuss solutions currently available within Phon and offer an outlook on future methodological and technical developments in the area of clinical phonology. This article includes a step-by-step introduction to Phon suitable for readers who lack previous experience with the software. We conclude with a discussion of data sharing and its vital role in advancing research and intervention practices in the area of speech development and disorders., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Spoken language is a central part of our everyday lives, but the precise roles that individual cortical regions play in the production of speech are often poorly understood. To address this issue, we focally lowered the temperature of distinct cortical regions in awake neurosurgical patients, and we relate this perturbation to changes in produced speech sequences. Using this method, we confirm that speech is highly lateralized, with the vast majority of behavioral effects seen on the left hemisphere. We then use this approach to demonstrate a clear functional dissociation between nearby cortical speech sites. Focal cooling of pars triangularis/pars opercularis (Broca's region) and the ventral portion of the precentral gyrus (speech motor cortex) resulted in the manipulation of speech timing and articulation, respectively. Our results support a class of models that have proposed distinct processing centers underlying motor sequencing and execution for speech., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To describe the experience and outcome of performing whole-exome sequencing (WES) for resolution of patients on a diagnostic odyssey in the first 18 months of an individualized medicine clinic (IMC)., Patients and Methods: The IMC offered WES to physicians of Mayo Clinic practice for patients with suspected genetic disease. DNA specimens of the proband and relatives were submitted to WES laboratories. We developed the Genomic Odyssey Board with multidisciplinary expertise to determine the appropriateness for IMC services, review WES reports, and make the final decision about whether the exome findings explain the disease. This study took place from September 30, 2012, to March 30, 2014., Results: In the first 18 consecutive months, the IMC received 82 consultation requests for patients on a diagnostic odyssey. The Genomic Odyssey Board deferred 7 cases and approved 75 cases to proceed with WES. Seventy-one patients met with an IMC genomic counselor. Fifty-one patients submitted specimens for WES testing, and the results have been received for all. There were 15 cases in which a diagnosis was made on the basis of WES findings; thus, the positive diagnostic yield of this practice was 29%. The mean cost per patient for this service was approximately $8000. Medicaid supported 27% of the patients, and 38% of patients received complete or partial insurance coverage., Conclusion: The significant diagnostic yield, moderate cost, and notable health marketplace acceptance for WES compared with conventional genetic testing make the former method a rational diagnostic approach for patients on a diagnostic odyssey., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Children with residual speech errors face an increased risk of social, emotional, and/or academic challenges relative to their peers with typical speech. Previous research has shown that the effects of speech sound disorder may persist into adulthood and span multiple domains of activity limitations and/or participation restrictions, as defined by the World Health Organization's International Classification of Functioning, Disability and Health model. However, the nature and extent of these influences varies widely across children. This study aimed to expand the evidence base on the social, emotional, and academic impact of residual speech errors by collecting survey data from parents of children receiving treatment for /r/ misarticulation. By examining the relationship between an overall measure of impact (weighted summed score) and responses to 11 survey items, the present study offers preliminary suggestions for factors that could be considered when making decisions pertaining to treatment allocation in this population., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To understand motivations, educational needs, and concerns of individuals contemplating whole-exome sequencing (WES) and determine what amount of genetic information might be obtained by sequencing a generally healthy cohort so as to more effectively counsel future patients., Patients and Methods: From 2012 to 2014, 40 medically educated, generally healthy scientists at Mayo Clinic were invited to have WES conducted on a research basis; 26 agreed to be in a drawing from which 10 participants were selected. The study involved pre- and posttest genetic counseling and completion of 4 surveys related to the experience and outcomes. Whole-exome sequencing was conducted on DNA from blood from each person., Results: Most variants (76,305 per person; range, 74,505-77,387) were known benign allelic variants, variants in genes of unknown function, or variants of uncertain significance in genes of known function. The results of suspected pathogenic/pathogenic variants in Mendelian disorders and pharmacogenomic variants were disclosed. The mean number of suspected pathogenic/pathogenic variants was 2.2 per person (range, 1-4). Four pharmacogenomic genes were included for reporting; variants were found in 9 of 10 participants., Conclusion: This study provides data that may be useful in establishing reality-based patient expectations, outlines specific points to cover during counseling, and increases confidence in the feasibility of providing adequate preparation and counseling for WES in generally healthy individuals., (Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

This paper investigates a proposed phonetically-based account of developmental phonological patterns that lack counterparts in adult typology. Adult listeners perceive some phonemic contrasts more accurately than others, and these differences in perceptual recoverability are posited to represent one influence on phonological typology. One hypothesis suggests that children and adults could differ in their patterns of relative perceptual sensitivity, and these differences could form the basis for some child-specific phonological patterns in production. However, there has been a lack of empirical evidence to support this claim. This study used a nonword discrimination task to investigate differences in perceptual recoverability across contrasts and contexts in typically-developing preschool children. Participants heard nonwords that were identical or differed by a single segment in initial or final position. Results revealed general agreement between child and adult listeners in the relative discriminability of different featural contrasts. For certain contrasts, discrimination accuracy was significantly greater in initial than final position, mirroring an asymmetry seen in adults. Overall, these results suggest that perceptual discrimination in preschool-aged children is broadly congruent with patterns of relative sensitivity observed in adult listeners. These findings suggest that factors other than perceptual recoverability should be explored to account for child-specific phonological patterns.

Biofeedback intervention can help children achieve correct production of a treatment-resistant error sound, but generalisation is often limited. This case study suggests that generalisation can be enhanced when biofeedback intervention is structured in accordance with a "challenge point" framework for speech-motor learning. The participant was an 11-year-old with residual /r/ misarticulation who had previously attained correct /r/ production through a structured course of ultrasound biofeedback treatment but did not generalise these gains beyond the word level. Treatment difficulty was adjusted in an adaptive manner following predetermined criteria for advancing, maintaining, or moving back a level in a multidimensional hierarchy of functional task complexity. The participant achieved and maintained virtually 100% accuracy in producing /r/ at both word and sentence levels. These preliminary results support the efficacy of a semi-structured implementation of the challenge point framework as a means of achieving generalisation and maintenance of treatment gains.

Purpose: To document the efficacy of ultrasound biofeedback treatment for misarticulation of the North American English rhotic in children. Because of limited progress in the first cohort, a series of two closely related studies was conducted in place of a single study. The studies differed primarily in the nature of tongue-shape targets (e.g., retroflex, bunched) cued during treatment., Method: Eight participants received 8 weeks of individual ultrasound biofeedback treatment targeting rhotics. In Study 1, all 4 participants were cued to match a bunched tongue-shape target. In Study 2, participants received individualized cues aimed at eliciting the tongue shape most facilitative of perceptually correct rhotics., Results: Participants in Study 1 showed only minimal treatment effects. In Study 2, all participants demonstrated improved production of rhotics in untreated words produced without biofeedback, with large to very large effect sizes., Conclusions: The results of Study 2 indicate that with proper parameters of treatment, ultrasound biofeedback can be a highly effective intervention for children with persistent rhotic errors. In addition, qualitative comparison of Studies 1 and 2 suggests that treatment for the North American English rhotic should include opportunities to explore different tongue shapes, to find the most facilitative variant for each individual speaker.

There is increasing recognition that genomic medicine as part of individualized medicine has a defined role in patient care. Rapid advances in technology and decreasing cost combine to bring genomic medicine closer to the clinical practice. There is also growing evidence that genomic-based medicine can advance patient outcomes, tailor therapy and decrease side effects. However the challenges to integrate genomics into the workflow involved in patient care remain vast, stalling assimilation of genomic medicine into mainstream medical practice. In this review we describe the approach taken by one institution to further individualize medicine by offering, executing and interpreting whole exome sequencing on a clinical basis through an enterprise-wide, standalone individualized medicine clinic. We present our experience designing and executing such an individualized medicine clinic, sharing lessons learned and describing early implementation outcomes., (© 2014 Wiley Periodicals, Inc.)

Purpose: Misarticulation of /r/ is among the most challenging developmental speech errors to remediate. Case studies suggest that visual biofeedback treatment can establish perceptually accurate /r/ in clients who have not responded to traditional treatments. This investigation studied the response of children with persistent /r/ misarticulation to a course of traditional treatment and a course of biofeedback treatment., Method: Eleven children with /r/ misarticulation completed 10 weeks of individual treatment consisting of 4-6 weeks of traditional treatment followed by 4-6 weeks of biofeedback treatment. Progress was measured by tracking correct /r/ productions within treatment and probing /r/ in words at 3 time points., Results: At the group level, there was no difference in independent judges' ratings of /r/ sounds produced by the children before and after traditional treatment. However, /r/ sounds produced after biofeedback treatment were significantly more likely to be rated by the judges as perceptually correct. Eight of the 11 children made measurable gains in the accuracy of isolated /r/ produced within treatment, with 4 showing significant generalization to untreated /r/ in words., Conclusion: This descriptive study shows that treatment incorporating spectral biofeedback can facilitate accurate /r/ production in children with treatment-resistant errors. A follow-up period using traditional intervention methods may be necessary to encourage generalization.

Many children who neutralize phonemic contrasts in production exhibit diminished perception of the same contrasts. It is usually difficult to determine whether the perception deficit caused the production error, or vice versa; however, the direction of causation has implications for treatment planning. This study examines perception-production relationships in the phenomenon of neutralization in strong position, where children neutralize only in perceptually salient contexts. To test a hypothesis that this phenomenon arises from a child-specific pattern of perceptual sensitivity, a non-word discrimination task was administered to a 4-year-old boy with neutralization in strong position in production. Contrary to the perceptual hypothesis, his discrimination accuracy was greatest for contrasts in initial/strong position, where his production errors occurred. Independent of position, however, his perception of a phonemic contrast he neutralized was decreased relative to other contrasts. This case is argued to constitute evidence that a primary production deficit can cause decreased perceptual ability.