Use Of Genomic Technologies Research Articles

Next generation sequencing study in a cohort of Italian patients with syndromic hearing loss

Hearing loss (HL), one of the most common congenital disorder, affects about one child in 1000. Among the genetic forms of HL, ∼30% of the cases are associated with other signs or symptoms, leading to Syndromic Hearing Loss (SHL) with about 700 different forms described so far.In this report, we refer the clinical and molecular data of 38 Italian SHL unrelated patients, and their relatives, affected by the most common syndromes associated with HL (i.e., Usher, Pendred, Charge, Waardenburg, Alport, Stickler, Branchiootorenal and Microdeletions syndromes). Patients have been analysed using next-generation sequencing (NGS) and High Density (HD)-SNP array technologies. Data analysis led to the identification of nine novel and 27 known causative mutations in 12 genes and two microdeletions in chromosomes 1 and 10, respectively.In particular, as regards to Usher syndrome, that affects 32% of our patients, we were able to reach a molecular diagnosis in 83% of the cases and to identify in Northern Eastern Italy a very common USH2A gene mutation (39%) (c.11864G > A, p.(Trp3955*) which can be defined “Central-Eastern European allele.”As regards to Alport syndrome, we were able to potentially reclassify a pathogenic allele in the COL4A3 gene, previously associated only with benign familial hematuria.In all the other cases, the genomic analysis allowed us to confirm the role of known causative genes and to identify several novel and known alleles.Overall, our results highlight the effectiveness of combining an accurate clinical characterization with the use of genomic technologies (NGS and SNP arrays) for the molecular diagnosis of SHL, with a clear positive impact in the management and treatment of all the patients.

Genomic Testing for Human Health and Disease Across the Life Cycle: Applications and Ethical, Legal, and Social Challenges.

The expanding use of genomic technologies encompasses all phases of life, from the embryo to the elderly, and even the posthumous phase. In this paper, we present the spectrum of genomic healthcare applications, and describe their scope and challenges at different stages of the life cycle. The integration of genomic technology into healthcare presents unique ethical issues that challenge traditional aspects of healthcare delivery. These challenges include the different definitions of utility as applied to genomic information; the particular characteristics of genetic data that influence how it might be protected, used and shared; and the difficulties applying existing models of informed consent, and how new consent models might be needed.

The Expectations and Challenges of Wildlife Disease Research in the Era of Genomics: Forecasting with a Horizon Scan-like Exercise.

The outbreak and transmission of disease-causing pathogens are contributing to the unprecedented rate of biodiversity decline. Recent advances in genomics have coalesced into powerful tools to monitor, detect, and reconstruct the role of pathogens impacting wildlife populations. Wildlife researchers are thus uniquely positioned to merge ecological and evolutionary studies with genomic technologies to exploit unprecedented "Big Data" tools in disease research; however, many researchers lack the training and expertise required to use these computationally intensive methodologies. To address this disparity, the inaugural "Genomics of Disease in Wildlife" workshop assembled early to mid-career professionals with expertise across scientific disciplines (e.g., genomics, wildlife biology, veterinary sciences, and conservation management) for training in the application of genomic tools to wildlife disease research. A horizon scanning-like exercise, an activity to identify forthcoming trends and challenges, performed by the workshop participants identified and discussed 5 themes considered to be the most pressing to the application of genomics in wildlife disease research: 1) "Improving communication," 2) "Methodological and analytical advancements," 3) "Translation into practice," 4) "Integrating landscape ecology and genomics," and 5) "Emerging new questions." Wide-ranging solutions from the horizon scan were international in scope, itemized both deficiencies and strengths in wildlife genomic initiatives, promoted the use of genomic technologies to unite wildlife and human disease research, and advocated best practices for optimal use of genomic tools in wildlife disease projects. The results offer a glimpse of the potential revolution in human and wildlife disease research possible through multi-disciplinary collaborations at local, regional, and global scales.

Sequencing Newborns: A Call for Nuanced Use of Genomic Technologies.

Many scientists and doctors hope that affordable genome sequencing will lead to more personalized medical care and improve public health in ways that will benefit children, families, and society more broadly. One hope in particular is that all newborns could be sequenced at birth, thereby setting the stage for a lifetime of medical care and self-directed preventive actions tailored to each child's genome. Indeed, commentators often suggest that universal genome sequencing is inevitable. Such optimism can come with the presumption that discussing the potential limits, cost, and downsides of widespread application of genomic technologies is pointless, excessively pessimistic, or overly cautious. We disagree. Given the pragmatic challenges associated with determining what sequencing data mean for the health of individuals, the economic costs associated with interpreting and acting on such data, and the psychosocial costs of predicting one's own or one's child's future life plans based on uncertain testing results, we think this hope and optimism deserve to be tempered. In the analysis that follows, we distinguish between two reasons for using sequencing: to diagnose individual infants who have been identified as sick and to screen populations of infants who appear to be healthy. We also distinguish among three contexts in which sequencing for either diagnosis or screening could be deployed: in clinical medicine, in public health programs, and as a direct-to-consumer service. Each of these contexts comes with different professional norms, policy considerations, and public expectations. Finally, we distinguish between two main types of genome sequencing: targeted sequencing, where only specific genes are sequenced or analyzed, and whole-exome or whole-genome sequencing, where all the DNA or all the coding segments of all genes are sequenced and analyzed. In a symptomatic newborn, targeted or genome-wide sequencing can help guide other tests for diagnosis or for specific treatment that is urgently needed. Clinicians use the infant's symptoms (or phenotype) to interrogate the sequencing data. These same complexities and uncertainties, however, limit the usefulness of genome-wide sequencing as a population screening tool. While we recognize considerable benefit in using targeted sequencing to screen for or detect specific conditions that meet the criteria for inclusion in newborn screening panels, use of genome-wide sequencing as a sole screening tool for newborns is at best premature. We conclude that sequencing technology can be beneficially used in newborns when that use is nuanced and attentive to context.

Myth: All calves are created equal

The value of commercial cattle, both feeder cattle and replacement females, has traditionally been imperfect as it was basically based on weight and it did not realize the potential value differences of those pounds. Historically, the "reputation" of cattle was limited without facts and true value for the system of beef production. Characterization of cattle genetic merit in the commercial cow herd today allows value differentiation. No longer are calves valued strictly on a weaned calf-weight and price. Selection tools that were typically associated with breed organizations and purchases of registered seedstock can be extended to quantifying genetic value in commercial herds. The use of genomic technology provides metrics for growth and carcass traits to better describe genetic potential for commercial calves. Allied industry delivers DNA tests that can assist commercial producers improve calf crop genetics and value-based marketing options for calf crops. Veterinarians can play a key role in assisting their clientele with sample collection, cow-herd record assessment, and interpretation of genomic results as part of a complete whole-herd management system.

A proposed approach to accelerate evidence generation for genomic-based technologies in the context of a learning health system.

Genomic technologies should demonstrate analytical and clinical validity and clinical utility prior to wider adoption in clinical practice. However, the question of clinical utility remains unanswered for many genomic technologies. In this paper, we propose three building blocks for rapid generation of evidence on clinical utility of promising genomic technologies that underpin clinical and policy decisions. We define promising genomic tests as those that have proven analytical and clinical validity. First, risk-sharing agreements could be implemented between payers and manufacturers to enable temporary coverage that would help incorporate promising technologies into routine clinical care. Second, existing data networks, such as the Sentinel Initiative and the National Patient-Centered Clinical Research Network (PCORnet) could be leveraged, augmented with genomic information to track the use of genomic technologies and monitor clinical outcomes in millions of people. Third, endorsement and engagement from key stakeholders will be needed to establish this collaborative model for rapid evidence generation; all stakeholders will benefit from better information regarding the clinical utility of these technologies. This collaborative model can create a multipurpose and reusable national resource that generates knowledge from data gathered as part of routine care to drive evidence-based clinical practice and health system changes.

The elusive ideal of inclusiveness: lessons from a worldwide survey of neurologists on the ethical issues raised by whole-genome sequencing

The anticipation of ethical issues that may arise with the clinical use of genomic technologies is crucial to envision their future implementation in a manner sensitive to local contexts. Yet, populations in low- and middle-income countries are underrepresented in studies that aim to explore stakeholders’ perspectives on the use of such technologies. Within the framework of a research project entitled “Personalized medicine in the treatment of epilepsy”, we sought to increase inclusiveness by widening the reach of our survey, inviting neurologists from around the world to share their views and practices regarding the use of whole-genome sequencing in clinical neurology and its associated ethics. We discuss herein the compelling scientific and ethical reasons that led us to attempt to recruit neurologists worldwide, despite the lack, in many low- or middle-income countries, of access to genomic technologies. Recruitment procedures and their results are presented and discussed, as well as the barriers we faced. We conclude that inclusive recruitment remains a challenging, albeit necessary and legitimate, endeavour.

Genomic newborn screening: public health policy considerations and recommendations

BackgroundThe use of genome-wide (whole genome or exome) sequencing for population-based newborn screening presents an opportunity to detect and treat or prevent many more serious early-onset health conditions than is possible today.MethodsThe Paediatric Task Team of the Global Alliance for Genomics and Health’s Regulatory and Ethics Working Group reviewed current understanding and concerns regarding the use of genomic technologies for population-based newborn screening and developed, by consensus, eight recommendations for clinicians, clinical laboratory scientists, and policy makers.ResultsBefore genome-wide sequencing can be implemented in newborn screening programs, its clinical utility and cost-effectiveness must be demonstrated, and the ability to distinguish disease-causing and benign variants of all genes screened must be established. In addition, each jurisdiction needs to resolve ethical and policy issues regarding the disclosure of incidental or secondary findings to families and ownership, appropriate storage and sharing of genomic data.ConclusionThe best interests of children should be the basis for all decisions regarding the implementation of genomic newborn screening.

Cancer genomics guide clinical practice in personalized medicine

Targeted therapies have revolutionized the treatment of many cancers. Widely developed over the last decade, this new concept of precision medicine relies on the use of genomic technologies to analyze tumor samples in order to identify actionable targets and biomarkers of resistance. The goal is to optimize treatment by identifying which therapeutic approach is best for each patient, i.e. the treatment that is effective, has minimal adverse effects, and avoids unnecessary intervention and cost. The purpose of this review is to highlight, using a few seminal examples of therapeutic targets, the important contribution of appropriate analysis of key oncogenes or driver genes in making clinical decisions. Cancer genomics is now an indispensable part of clinical management. Furthermore, the development of next generation sequencing (NGS) will enable exploration of more and more genes of interest, leading to new treatment options for personalized medicine.

Primer in Genetics and Genomics, Article 2-Advancing Nursing Research With Genomic Approaches.

Nurses investigate reasons for variable patient symptoms and responses to treatments to inform how best to improve outcomes. Genomics has the potential to guide nursing research exploring contributions to individual variability. This article is meant to serve as an introduction to the novel methods available through genomics for addressing this critical issue and includes a review of methodological considerations for selected genomic approaches. This review presents essential concepts in genetics and genomics that will allow readers to identify upcoming trends in genomics nursing research and improve research practice. It introduces general principles of genomic research and provides an overview of the research process. It also highlights selected nursing studies that serve as clinical examples of the use of genomic technologies. Finally, the authors provide suggestions about how to apply genomic technology in nursing research along with directions for future research. Using genomic approaches in nursing research can advance the understanding of the complex pathophysiology of disease susceptibility and different patient responses to interventions. Nurses should be incorporating genomics into education, clinical practice, and research as the influence of genomics in health-care research and practice continues to grow. Nurses are also well placed to translate genomic discoveries into improved methods for patient assessment and intervention.

A missing link in the bench-to-bedside paradigm: engaging regulatory stakeholders in clinical genomics research.

Editorial summaryFor genomic medicine research to be fully translated into clinical care, it is critical for researchers to engage stakeholders who ultimately regulate the use of genomic technologies and therapeutics within healthcare practice. Herein, we describe an example of how this might work.

Patterns of Kingella kingae Disease Outbreaks.

Kingella kingae outbreaks occur sporadically in childcare centers but remain poorly understood and difficult to identify. To provide the basis of a better knowledge of K. kingae outbreaks patterns that may help to guide identification and management strategies, we collected epidemiological, clinical and laboratory data from all reported K. kingae outbreaks, and those from 2 new Israel outbreaks in 2014. Nine outbreaks were identified in the USA, Israel and France from 2003 to 2014. Twenty-seven children with a median age of 14 ± 4.1 months were affected, male:female ratio of 1.4:1. Outbreaks demonstrated seasonal patterns from the 10th to the 45th weeks, a mean duration of 13.1 ± 8.4 days, a mean attack rate of 17.3 ± 5.1% and a case-fatality rate of 3.7% (1/27). Seventy-four percentage of children had fever (20/27), and the mean values of white blood cell count and C-reactive protein level were 14.6 ± 4.5 × 10/L and 23.8 ± 24.1 mg/L, respectively. Osteoarticular infections accounted for 88.9% of cases (24/27), bacteremia 7.4% (2/27), endocarditis 3.7% (1/27) and meningitis 3.7% (1/27). Specific real-time polymerase chain reaction demonstrated higher performance than culture methods in the diagnosis of case patients and investigations of oropharyngeal K. kingae carriage among close contacts, and multilocus sequence typing methods revealed that ST-6 and ST-25 invasive strains were responsible for multiple country-dependent outbreaks. Coviral infections were identified in the majority of K. kingae outbreaks, notably those causing oral ulcers. K. kingae outbreaks displayed severe K. kingae diseases that were poorly confirmed with culture methods. We argue for the use of genomic technologies to investigate further K. kingae outbreaks.

Patient uptake and satisfaction with advanced genomic technologies offered through an employee benefit program.

72 Background: Access to advanced genomic technologies for the diagnosis and treatment of cancer is important. As part of an employee benefit program, we offered genomic technologies, such as somatic tumor and inherited germline genetic testing, as well as clinical trial information, medical second opinions, and genetic counseling, as appropriate, to enrollees with cancer. Genetic counselors served as cancer navigators through the process. The study aimed to assess uptake of the services offered and satisfaction with the program. Methods: Established benefit enrollment criteria included a diagnosis of cancer and company status (employee, spouse, dependent child). All data and communications were tracked in an online Patient Resource Management (PRM) system. Data was pulled directly from the PRM system logs. To measure satisfaction, participants were asked to complete an anonymous exit survey following completion of the program. Results: The data set included 131 individuals who inquired about program services. Eighty of the 131 (61%) met criteria and enrolled. Thirty-six of the 80 (45%) had complete data available for analysis. Cancer types varied but mostly included breast, colon, lung, leukemia and lymphoma. The table below shows the specific service uptake rates for the cohort. Seven participants completed the exit survey and all responded that the information gained from the program was useful and that the program increased satisfaction with their employer. Conclusions: Patients with cancer do not always have access to genomic technologies, nor understand the technology applications for their prognosis and treatment. Our experience in developing this program is that enrollees were interested in pursuing services that supported the use of genomic technologies, and satisfaction was high amongst those that provided feedback. Overall, the program directly engaged participants in their care and empowered them through education provided by genetic counselor navigators in ways that are not typically available in most cancer care settings. [Table: see text]

Genomics in research and health care with Aboriginal and Torres Strait Islander peoples.

Genomics is increasingly becoming an integral component of health research and clinical care. The perceived difficulties associated with genetic research involving Aboriginal and Torres Strait Islander people mean that they have largely been excluded as research participants. This limits the applicability of research findings for Aboriginal and Torres Strait Islander patients. Emergent use of genomic technologies and personalised medicine therefore risk contributing to an increase in existing health disparities unless urgent action is taken. To allow the potential benefits of genomics to be more equitably distributed, and minimise potential harms, we recommend five actions: (1) ensure diversity of participants by implementing appropriate protocols at the study design stage; (2) target diseases that disproportionately affect disadvantaged groups; (3) prioritise capacity building to promote Indigenous leadership across research professions; (4) develop resources for consenting patients or participants from different cultural and linguistic backgrounds; and (5) integrate awareness of issues relating to Indigenous people into the governance structures, formal reviews, data collection protocols and analytical pipelines of health services and research projects.

Cancer immunotherapy out of the gate: the 22nd annual Cancer Research Institute International Immunotherapy Symposium.

The 22nd annual Cancer Research Institute (CRI) International Immunotherapy Symposium was held from October 5-8, 2014, in New York City. Titled "Cancer Immunotherapy: Out of the Gate," the symposium began with a Cancer Immunotherapy Consortium satellite meeting focused on issues in immunotherapy drug development, followed by five speaker sessions and a poster session devoted to basic and clinical cancer immunology research. The second annual William B. Coley lecture was delivered by Lieping Chen, one of the four recipients of the 2014 William B. Coley Award for Distinguished Research in Tumor Immunology; the other three recipients were Gordon Freeman, Tasuku Honjo, and Arlene Sharpe. Prominent themes of the conference were the use of genomic technologies to identify neoantigens and the emergence of new immune modulatory molecules, beyond CTLA-4 and PD-1/PD-L1, as new therapeutic targets for immunotherapy.

"Not Tied Up Neatly with a Bow": Professionals' Challenging Cases in Informed Consent for Genomic Sequencing.

As the use of genomic technology has expanded in research and clinical settings, issues surrounding informed consent for genome and exome sequencing have surfaced. Despite the importance of informed consent, little is known about the specific challenges that professionals encounter when consenting patients or research participants for genomic sequencing. We interviewed 29 genetic counselors and research coordinators with considerable experience obtaining informed consent for genomic sequencing to understand their experiences and perspectives. As part of this interview, 24 interviewees discussed an informed consent case they found particularly memorable or challenging. We analyzed these case examples to determine the primary issue or challenge represented by each case. Challenges fell into two domains: participant understanding, and facilitating decisions about testing or research participation. Challenges related to participant understanding included varying levels of general and genomic literacy, difficulty managing participant expectations, and contextual factors that impeded participant understanding. Challenges related to facilitating decision-making included complicated family dynamics such as disagreement or coercion, situations in which it was unclear whether sequencing research would be a good use of participant time or resources, and situations in which the professional experienced disagreement or discomfort with participant decisions. The issues highlighted in these case examples are instructive in preparing genetics professionals to obtain informed consent for genomic sequencing.

Can genomic medicine improve financial sustainability of health systems?

Recent years have seen increased use of genomic technologies in a variety of research and clinical settings. Genomic medicine is not a cost-containment measure per se, but is viewed as having the potential to bend the healthcare cost curve. Currently, it is unknown how systematic adoption of genomic medicine in clinical practice will impact healthcare costs. This article discusses the potential economic impact of genomic medicine and the challenges that lie ahead.

Abstract A41: Automated retrieval and assessment of biomarker-related evidence for cancer treatment decision support

Abstract Introduction: Molecular characterization is rapidly becoming a standard of care in clinical oncology practice. Simultaneously, growing volumes of peer-reviewed literature reporting the relationships between genomic aberrations, tumor responsiveness to treatments, and associated patient outcomes has significantly increased the challenge facing clinicians to comprehensively identify and prioritize personalized treatments. This challenge is further compounded by a) the disease-specific nature of most predictive biomarkers, b) discordant published observations, c) the varying levels of clinical validity associated with most biomarker:drug response relationships, and d) the time constraints that all treating oncologists face. To overcome such challenges, we developed an automated computational system to assess the predicted effects of published genomic aberrations on drug responsiveness in a patient/disease-specific manner. Here we describe how computational selection and assessment of peer-reviewed published evidence relevant to a given cancer patient compares to that of a human expert with access to the same body of data. Methods: We developed a computational treatment decision support system (TDSS) for the analysis of cancer patients with a set of known mutations. The system holds a drug-response database (DRDB) containing expert curated information on three levels of clinical validity: 1) clinically endorsed (>100 FDA-approved facts), 2) clinically observed (>5,000 patients), and 3) translationally observed (∼4,000 model systems). Given a patient mutation profile, the TDSS retrieves related DRDB entries and weighs them according to validity level, relationship to patient disease (using the Medical Subject Headings ontology, MeSH), and RECIST response criteria. The TDSS then summarizes whether a given genotype is likely to confer response or resistance to available cancer drugs. To compare the performance of this system to that of a human molecular diagnostics expert, we created 48 virtual patients, each from one of five highly frequent cancer indications (lung, CRC, GIST, melanoma, breast) and with one or two randomly drawn predictive mutations. They were both processed by the TDSS and surveyed by an expert with electronically access to all DRDB data. The task was to recommend up to three treatments with highest likelihood of response, and identify up to three with highest risk of resistance for each case. Results: The TDSS required a few seconds of computation, compared to more than five hours of work by the expert. Both obtained a similar number of actionable predictions, for essentially the same 75% of the cases. For each case, the three treatments selected for response / resistance were compared and critically re-assessed. We found the error rates to be higher for the molecular diagnostics expert (9.6% of treatments for response, 2.1% for resistance) than for the TDSS (3.0% response, 1.4% resistance). Frequent causes of human error include a) overlooking evidence and b) failure to consider the numbers of patient cases observed. Conclusions: Computational aggregation and rules-based analysis of the clinical effects of tumor mutations on cancer drug responsiveness can greatly aid the evidence-based prioritization of treatment options for cancer patients with superior accuracy and turn-around-times. While a large-scale study is planned to compare TDSS performance against multiple experts in a real-life clinical setting, our preliminary insights suggest that the necessity for such computational systems will parallel both the emergence of clinico-molecular knowledge in this domain and the adoption rates for clinical use of genomic technologies. Citation Format: Alexander Zien, Francesca Diella, Anja Doerks, Theodoros Soldatos, Markus Hartenfeller, David B. Jackson. Automated retrieval and assessment of biomarker-related evidence for cancer treatment decision support. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A41.

'Good soldiers are made, not born'⊥: the dangers of medicalizing ability in the military use of genetics.

Advances in genetic and genomic science are of particular interest to the United States military. Responding to Maxwell J. Mehlman's and Tracy Yeheng Li's article Ethical, Legal, Social, and Policy Issues in the Use of Genomic Technology by the U.S. Military, this Commentary explores the social consequences of medicalizing what it means to be a good soldier. It begins by reviewing the well-documented consequences of medicalization in the contexts of the eugenics movement and modern genetic and genomic science. It then applies that analysis to the military use of genetics and genomics, focusing on the ways in which genetic or genomic accounts of military ability could entrench existing gender and racial disparities.

Yesterday's war; tomorrow's technology: peer commentary on 'Ethical, legal, social and policy issues in the use of genomic technologies by the US military'.

A recent article by Maxwell J. Mehlman and Tracy Yeheng Li, in the Journal of Law and the Biosciences, sought to examine the ethical, legal, social, and policy issues associated with the use of genetic screening and germ-line therapies (‘genomic technologies’) by the US Military. In this commentary, we will elaborate several related matters: the relationship between genetic and non-genetic screening methods, the history of selection processes and force strength, and the consequences and ethics of, as Mehlman and Li suggest, engineering enhanced soldiers. We contend, first, that the strengths of genomic testing as a method of determining enrollment in the armed forces has limited appeal, given the state of current selection methods in the US armed forces. Second, that the vagaries of genetic selection, much like other forms of selection that do not bear causally or reliably on soldier performance (such as race, gender, and sexuality), pose a systematic threat to force strength by limiting the (valuable) diversity of combat units. Third, that the idea of enhancing warfighters through germ-line interventions poses serious ethical issues in terms of the control and ownership of ‘enhancements’ when members separate from service.