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Purpose: To develop and evaluate a scalable national program to build confidence, competence and capability in the use of rapid genomic testing (rGT) in the acute pediatric setting., Methods: We used theory-informed approaches to design a modular, adaptive program of blended learning aimed at diverse professional groups involved in acute pediatric care. The program comprised 4 online learning modules and an online workshop and was centered on case-based learning. We evaluated the program using the Kirkpatrick 4-level model of training evaluation and report our findings using the Reporting Item Standards for Education and its Evaluation (RISE2) guidelines for genomics education and evaluation., Results: Two hundred and two participants engaged with at least 1 component of the program. Participants self-reported increased confidence in using rGT, (P < .001), and quiz responses objectively demonstrated increased competence (eg, correct responses to a question on pretest counseling increased from 30% to 64%; P < .001). Additionally, their capability in applying genomic principles to simulated clinical cases increased (P < .001), as did their desire to take on more responsibility for performing rGT. The clinical interpretation of more complex test results (such as negative results or variants of uncertain significance) appeared to be more challenging, indicating a need for targeted education in this area., Conclusion: The program format was effective in delivering multidisciplinary and wide-scale genomics education in the acute care context. The modular approach we have developed now lends itself to application in other medical specialties or areas of health care., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

On May 23-24, 2024, the 1 st Spanish Conference on Genomic Medicine convened in Madrid, Spain. An international and multidisciplinary group of experts gathered to discuss the current state and prospects of genomic medicine in the Spanish-speaking world. There were 278 attendees from Latin America, US, UK, Germany, and Spain, and the topics covered included rare diseases, genome medicine in national health systems (NHSs), artificial intelligence, and commercial development ventures. One particular area of attention was our still sketchy understanding of genome variants. This is evidenced by the fact that many diagnoses in rare diseases continue to yield odysseys that take years, with up to 50% of cases that may go undiagnosed. Since a lot of the genome remains to poorly understood, as new technologies such as long read sequencing become more ubiquitous and cheaper, it is expected that current gaps in genome references will improve. However, disparities within the NHSs suggest that advancements do not necessarily rely on resources but the appropriate regulation and pathways for education of professionals being properly implemented. This is where Genomics England can be a clinical genomic implementation example for routine health care. Ethical challenges, including privacy, informed consent, equity, representation, and genetic discrimination, also require the need for robust legal frameworks and culturally sensitive practices. The future of genomics in Spanish-speaking countries depends on addressing all of these issues. By navigating these challenges responsibly, Spanish-speaking countries can harness the power of genomics to improve health outcomes and advance scientific knowledge, ensuring that the benefits of personalized medicine are realized in an inclusive and equitable manner.

Purpose: Critically ill infants from marginalized populations disproportionately receive care in neonatal intensive care units (NICUs) that lack access to state-of-the-art genomic care, leading to inequitable outcomes. We sought provider perspectives to inform our implementation study (VIGOR) providing rapid genomic sequencing within these settings., Methods: We conducted semistructured focus groups with neonatal and genetics providers at 6 NICUs at safety-net hospitals, informed by the Promoting Action on Research Implementation in Health Services framework, which incorporates evidence, context, and facilitation domains. We iteratively developed codes and themes until thematic saturation was reached., Results: Regarding evidence, providers felt that genetic testing benefits infants and families. Regarding context, the major barriers identified to genomic care were genetic testing cost, lack of genetics expertise for disclosure and follow-up, and navigating the complexity of selecting and ordering genetic tests. Providers had negative feelings about the current status quo and inequity in genomic care across NICUs. Regarding facilitation, providers felt that a virtual support model such as VIGOR would address major barriers and foster family-centered care and collaboration., Conclusion: NICU providers at safety-net hospitals believe that access to state-of-the-art genomic care is critical for optimizing infant outcomes; yet, substantial barriers exist that the VIGOR study may address., Competing Interests: Conflict of Interest Monica H. Wojcik has consulted for Illumina and Sanofi and received speaking honoraria from GeneDx and Illumina. Pankaj B. Agrawal has consulted for Illumina and GeneDx. All other authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

A health workforce capable of implementing genomic medicine requires effective genomics education. Genomics education interventions developed for health professions over the last two decades, and their impact, are variably described in the literature. To inform an evaluation framework for genomics education, we undertook an exploratory scoping review of published needs assessments for, and/or evaluations of, genomics education interventions for health professionals from 2000 to 2023. We retrieved and screened 4,659 records across the two searches with 363 being selected for full-text review and consideration by an interdisciplinary working group. 104 articles were selected for inclusion in the review-60 needs assessments, 52 genomics education evaluations, and eight describing both. Included articles spanned all years and described education interventions in over 30 countries. Target audiences included medical specialists, nurses/midwives, and/or allied health professionals. Evaluation questions, outcomes, and measures were extracted, categorized, and tabulated to iteratively compare measures across stages of genomics education evaluation: planning (pre-implementation), development and delivery (implementation), and impact (immediate, intermediate, or long-term outcomes). They are presented here along with descriptions of study designs. We document the wide variability in evaluation approaches and terminology used to define measures and note that few articles considered downstream (long-term) outcomes of genomics education interventions. Alongside the evaluation framework for genomics education, results from this scoping review form part of a toolkit to help educators to undertake rigorous genomics evaluation that is fit for purpose and can contribute to the growing evidence base of the contribution of genomics education in implementation strategies for genomic medicine., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Implementation of genomic medicine into healthcare requires a workforce educated through effective educational approaches. However, ascertaining the impact of genomics education activities or resources is limited by a lack of evaluation and inconsistent descriptions in the literature. We aim to support those developing genomics education to consider how best to capture evaluation data that demonstrate program outcomes and effectiveness within scope. Here, we present an evaluation framework that is adaptable to multiple settings for use by genomics educators with or without education or evaluation backgrounds. The framework was developed as part of a broader program supporting genomic research translation coordinated by the Australian Genomics consortium. We detail our mixed-methods approach involving an expert workshop, literature review and iterative expert input to reach consensus and synthesis of a new evaluation framework for genomics education. The resulting theory-informed and evidence-based framework encompasses evaluation across all stages of education program development, implementation and reporting, and acknowledges the critical role of stakeholders and the effects of external influences., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Genomic kidney conditions often have a long lag between onset of symptoms and diagnosis. To design a real time genetic diagnosis process that meets the needs of nephrologists, we need to understand the current state, barriers, and facilitators nephrologists and other clinicians who treat kidney conditions experience, and identify areas of opportunity for improvement and innovation., Methods: Qualitative in-depth interviews were conducted with nephrologists and internists from 7 health systems. Rapid analysis identified themes in the interviews. These were used to develop service blueprints and process maps depicting the current state of genetic diagnosis of kidney disease., Results: Themes from the interviews included the importance of trustworthy resources, guidance on how to order tests, and clarity on what to do with results. Barriers included lack of knowledge, lack of access, and complexity surrounding the case and disease. Facilitators included good user experience, straightforward diagnoses, and support from colleagues., Discussion: The current state of diagnosis of kidney diseases with genetic etiology is suboptimal, with information gaps, complexity of genetic testing processes, and heterogeneity of disease impeding efficiency and leading to poor outcomes. This study highlights opportunities for improvement and innovation to address these barriers and empower nephrologists and other clinicians who treat kidney conditions to access and use real time genetic information., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Purpose: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials., Methods: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts., Results: Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials)., Conclusion: Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers' coverage policies., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647)., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Improvements in sequencing technology coupled with dramatic declines in the cost of genome sequencing have led to a proportional growth in the size and number of genetic datasets since the release of the human genetic sequence by The Human Genome Project (HGP) international consortium. The HGP was undeniably a significant scientific success, a turning point in human genetics and the beginning of human genomics. This burst of genetic information has led to a greater understanding of disease pathology and the potential of employing this data to deliver more precise patient care. Hence, the recognition of high-penetrance disease-causing mutations which encode drivers of disease has made the management of most diseases more specific. Nonetheless, while genetic scores are becoming more extensively used, their application in the real world is expected to be limited due to the lack of diversity in the data used to construct them. Underrepresented populations, such as racial and ethnic minorities, low-income individuals, and those living in rural areas, often experience greater health disparities and worse health outcomes compared to the general population. These disparities are often the result of systemic barriers, such as poverty, discrimination, and limited access to healthcare. Addressing health inequity in underrepresented populations requires addressing the underlying social determinants of health and implementing policies and programs which promoted health equity and reduce disparities. This can include expanding access to affordable healthcare, addressing poverty and unemployment, and promoting policies that combat discrimination and racism., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diagnostic genomic sequencing generates unprecedented amounts of data. In addition to its primary use, this data could be used for a wide range of secondary purposes, including research and informing future healthcare for the data donor. These opportunities may require data to be shared with third parties. Although effective data sharing relies on public support, there are barriers which may prevent people from choosing to donate their genomic data and surprisingly few studies explore these barriers in depth. To address this need, this study aimed to qualitatively explore the Australian public's views and preferences for storing and sharing genomic data. Online focus groups were recorded, transcribed, and analysed using inductive content analysis. A total of 7 focus groups were conducted with 39 members of the Australian public ranging from 18 to 67 years of age. Participants were mostly supportive of genomic data being stored and shared for secondary purposes, recognising the potential benefits for individual health and wider medical research. However, some concerns were identified. Participants felt genomic data was particularly sensitive information, and raised the potential for discrimination, stigma, and other malicious uses of such data. Concerns for privacy and security of the data were also prevalent. Trustworthiness of data users was important when considering who genomic data should be shared with. Although participants were supportive of data being freely available to health professionals and researchers, they were opposed to insurance companies and employers accessing the data. There was greater controversy around sharing data with law enforcement and pharmaceutical companies. Participants recognised both benefits and harms to sharing with law enforcement. They were also cognizant of the dual purpose of pharmaceutical companies as both research and profit-driven organisations. Finally, participants expressed varying perspectives about sharing genomic data with family members, yet most agreed that explicit consent from the data donor should be required to share their information with relatives. This study highlighted several of the Australian public's perceived barriers and motivators for the storage and sharing of genomic data. Participants recognised both the benefits of collecting, storing and sharing such data widely but also the potential for harm from data misuse. While public acceptance of such endeavours is required to maximise the volume of data made available, the concerns around data access and security need to be addressed before this can occur. These findings also highlight the nuance and ethical complexity of decisions about who we should allow to access donated genomic data. These perspectives will be essential in helping to shape the way large-scale genomic data storage and sharing is developed and implemented in Australia, and internationally., Competing Interests: Declaration of competing interest Yan Meng is an associate at Analysis Group, Ltd. Research for this article was undertaken when she was working at the University of Melbourne. Julian Savulescu is a Partner Investigator on an Australian Research Council Linkage award (LP190100841, Oct 2020–2023) which involves industry partnership from Illumina. He does not personally receive any funds from Illumina. Julian Savulescu presented at a Genomic Prediction-organised webinar (2021), but received no payment or other benefits from Genomic Prediction Ltd. Julian Savulescu is a Bioethics Committee consultant for Bayer. The remaining authors declare no conflict of interest., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The great advances in the development of genomic technologies and their incorporation into routine clinical practice is bringing about a change in which an individual's genetic information is becoming increasingly relevant to their medical care. This is known as genomic medicine. Its implementation is not without barriers, including difficulties in the assessment and interpretation of genomic data, deficient training of professionals and patients in this field, unequal access to units with expertise, and a lack of professional profiles and infrastructures necessary for the incorporation of genomic technologies into routine clinical practice. This article reviews the advances and challenges of genomic medicine., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Purpose: Gene panels with a series of strict variant filtering rules are often used for clinical analysis of exomes and genomes. Panel sizes vary, affecting the test's sensitivity and specificity. We investigated the background rate of candidate variants in a population setting using gene panels developed to diagnose a range of heterogeneous monogenic diseases., Methods: We used the Gene2Phenotype database with the Variant Effect Predictor plugin to identify rare nonsynonymous variants in exome sequence data from 200,643 individuals in UK Biobank. We evaluated 5 clinically curated gene panels of varying sizes (50-1700 genes)., Results: Bigger gene panels resulted in more prioritized variants, varying from an average of approximately 0.3 to 3.5 variants per person. The number of individuals with prioritized variants varied linearly with coding sequence length for monoallelic genes (∼300 individuals per 1000 base pairs) and quadratically for biallelic genes, with notable outliers., Conclusion: Although large gene panels may be the best strategy to maximize diagnostic yield in genetically heterogeneous diseases, they frequently prioritize likely benign variants requiring follow up. Most individuals have ≥1 rare nonsynonymous variant in panels containing >500 disease genes. Extreme caution should be applied when interpreting candidate variants, particularly in the absence of relevant phenotypes., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

About 4 and a half years have passed since"Cancer Genome Medicine"was first mentioned in the Third Phase of the Basic Plan to Promote Cancer Control Programs that started in October 2017. Currently, cancer genomic medicine is being carried out by the cancer gene panel test, which is covered by public insurance, mainly at the 12 Cancer Genome Medicine Core Center Hospital designated nationwide by the Ministry of Health, Labor, and Welfare in Japan. Cancer genomic medicine has come to be positioned as a standard medical treatment. However, there are various challenges in operating an expert panel that professionally examines the results of the gene panel tests and reports treatment recommendations and secondary findings that suggest hereditary tumors. In addition, there is an urgent need to disseminate and educate healthcare professionals and patients about cancer genomic medicine. In this panel discussion on January 14, 2022, 10 panelists discussed how to solve these issues and the prospects for the future.

With the spread of cancer genomic medicine in Japan, the burden on expert panels is clearly increasing. Various factors, such as the conditions for calculation of reimbursement and the fact that the panels can only be conducted at core hospitals for cancer genomic medicine have contributed to this increase in the burden. This paper describes the challenges and future of expert panels in the implementation of cancer genomic medicine in Japan, based on the experience of our hospital.

Applications of genomics to population screening are expanding in the United States and internationally. Many of these programs are being implemented in the context of healthcare systems, mostly in a clinical research setting, but there are some emerging examples of clinical models. This review examines these genomic population screening programs to identify common features and differences in screened conditions, genomic technology employed, approach to results disclosure, health outcomes, financial models, and sustainability. The diversity of approaches provides opportunities to learn and better understand the optimal approach to implementation based on the contextual setting.

Actionability is an important concept in medicine that does not have a well-accepted standard definition, nor is there a general consensus on how to establish it. Medical actionability is often conflated with clinical utility, a related but distinct concept. This lack of clarity contributes to practice variation and inconsistent coverage decisions in genomic medicine, leading to the potential for systematic bias in the use of evidence-based interventions. We clarify how medical actionability and clinical utility are distinct and then discuss the spectrum of actionability, including benefits for the person, the family, and society. We also describe applications across the life course, including prediction, diagnosis, and treatment. Current challenges in assessing the medical actionability of identified genomic variants include gaps in the evidence, limited contexts with practice guidelines, and subjective aspects of medical actionability. A standardized and authoritative assessment of medical actionability is critical to implementing genomic medicine in a fashion that improves population health outcomes and reduces health disparities.

Background: The widespread clinical application of genome-wide sequencing has resulted in many new diagnoses for rare genetic conditions, but testing regularly identifies variants of uncertain significance (VUS). The remarkable rise in the amount of genomic data has been paralleled by a rise in the number of protein structures that are now publicly available, which may have clinical utility for the interpretation of missense and in-frame insertions or deletions., Methods: Within a UK National Health Service genomic medicine diagnostic laboratory, we investigated the number of VUS over a 5-year period that were evaluated using protein structural analysis and how often this analysis aided variant classification., Results: We found 99 novel missense and in-frame variants across 67 genes that were initially classified as VUS by our diagnostic laboratory using standard variant classification guidelines and for which further analysis of protein structure was requested. Evidence from protein structural analysis was used in the re-assessment of 64 variants, of which 47 were subsequently reclassified as pathogenic or likely pathogenic and 17 remained as VUS. We identified several case studies where protein structural analysis aided variant interpretation by predicting disease mechanisms that were consistent with the observed phenotypes, including loss-of-function through thermodynamic destabilisation or disruption of ligand binding, and gain-of-function through de-repression or escape from proteasomal degradation., Conclusions: We have shown that using in silico protein structural analysis can aid classification of VUS and give insights into the mechanisms of pathogenicity. Based on our experience, we propose a generic evidence-based workflow for incorporating protein structural information into diagnostic practice to facilitate variant classification., (© 2022. The Author(s).)

Significant disparities in the clinical usefulness of genomic information across diverse groups are due to underrepresentation in genetic databases and inequitable access to genetic services. Remedying disparities is immediately needed to ensure that genomic medicine is more equitable but will take a long-term commitment and active engagement of diverse communities., Competing Interests: Declaration of interests W.K.C. is a member of the scientific advisory board of the Regeneron Genetics Center and the board of directors of Prime Medicine., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants., Methods: RoR processes were developed and approved by each eMERGE institution's internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant's disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed., Results: Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052)., Conclusion: The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR., Competing Interests: Conflicts of Interest R.C.G. receives compensation for advising AIA, Applied Therapeutics, Humanity, and Verily and is a cofounder of Genome Medical, Inc, a technology and services company providing genetics expertise to patients, providers, employers, and care systems. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Les auteurs déclarent n’avoir aucun lien d’intérêts.

Background: Genetic/genomic testing (GGT) are useful tools for improving health and preventing diseases. Still, since GGT deals with sensitive personal information that could significantly impact a patient's life or that of their family, it becomes imperative to consider Ethical, Legal and Social Implications (ELSI). Thus, ELSI studies aim to identify and address concerns raised by genomic research that could affect individuals, their family, and society. However, there are quantitative and qualitative discrepancies in the literature to describe the elements that provide content to the ELSI studies and such problems may result in patient misinformation and harmful choices., Methods: We analyzed the major international documents published by international organizations to specify the parameters that define ELSI and the recognized criteria for GGT, which may prove useful for researchers, health professionals and policymakers. First, we defined the parameters of the ethical, legal and social fields in GGT to avoid ambiguities when using the acronym ELSI. Then, we selected nine documents from 44 relevant publications by international organizations related to genomic medicine., Results: We identified 29 ELSI sub-criteria concerning to GGT, which were organized and grouped within 10 minimum criteria: two from the ethical field, four from the legal field and four from the social field. An additional analysis of the number of appearances of these 29 sub-criteria in the analyzed documents allowed us to order them and to determine 7 priority criteria for starting to evaluate and propose national regulations for GGT., Conclusions: We propose that the ELSI criteria identified herein could serve as a starting point to formulate national regulation on personalized genomic medicine, ensuring consistency with international bioethical requirements., (© 2021. The Author(s).)

Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some research participants suggest that researchers should be returning actionable IRRs to participants., Competing Interests: The authors have declared that no competing interests exist.

Founder populations may be enriched with certain genetic variants of high clinical impact compared to nonfounder populations due to bottleneck events and genetic drift. Using exome sequencing (ES), we quantified the load of pathogenic variants that may be clinically actionable in 6136 apparently healthy adults living in the Lancaster, PA Old Order Amish settlement. We focused on variants in 78 genes deemed clinically actionable by the American College of Medical Genetics and Genomics (ACMG) or Geisinger's MyCode Health Initiative. ES revealed 3191 total variants among these genes including 480 nonsynonymous variants. After quality control and filtering, we applied the ACMG/AMP guidelines for variant interpretation and classified seven variants, across seven genes, as either pathogenic or likely pathogenic. Through genetic drift, all seven variants, are highly enriched in the Amish compared to nonfounder populations. In total, 14.7% of Lancaster Amish individuals carry at least one of these variants, largely explained by the 13% who harbor a copy of a single variant in APOB. Other studies report combined frequencies of pathogenic/likely pathogenic (P/LP) variants in actionable genes between 2.0% and 6.2% in outbred populations. The Amish population harbors fewer actionable variants compared to similarly characterized nonfounder populations but have a higher frequency of each variant identified, offering opportunities for efficient and cost-effective targeted precision medicine., (© 2021 Wiley Periodicals LLC.)

Feline genomic medicine can decode human variants of uncertain significance (VUSs). Telomere-to-telomere genome assemblies are feasible for all felid species, supporting genetic evolution and speciation studies. Their highly conserved genomic organization compared to humans suggests cats may also decipher the intergenic variation affecting the 3D chromosome structures influencing gene regulation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The increasing availability of large-scale, complex data has made research into how human genomes determine physiology in health and disease, as well as its application to drug development and medicine, an attractive field for artificial intelligence (AI) approaches. Looking at recent developments, we explore how such approaches interconnect and may conflict with needs for and notions of causal knowledge in molecular genetics and genomic medicine. We provide reasons to suggest that-while capable of generating predictive knowledge at unprecedented pace and scale-if and how these approaches will be integrated with prevailing causal concepts will not only determine the future of scientific understanding and self-conceptions in these fields. But these questions will also be key to develop differentiated policies, such as for education and regulation, in order to harness societal benefits of AI for genomic research and medicine., (© 2021 The Authors. BioEssays published by Wiley Periodicals LLC.)

Genomic information is poised to play an increasing role in clinical care, extending beyond highly penetrant genetic conditions to less penetrant genotypes and common disorders. But with this shift, the question of clinical utility becomes a major challenge. A collaborative effort is necessary to determine the information needed to evaluate different uses of genomic information and then acquire that information. Another challenge must also be addressed if that process is to provide equitable benefits: the lack of diversity of genomic data. Current genomic knowledge comes primarily from populations of European descent, which poses the risk that most of the human population will be shortchanged when health benefits of genomics emerge. These two challenges have defined my career as a geneticist and have taught me that solutions must start with dialogue across disciplinary and social divides.

This study compares the trajectories of recent scientific/intellectual movements (SIMs) in biomedicine: evidence-based medicine, translational medicine, precision medicine, personalized medicine, stratified medicine, and genomic medicine. Drawing on bibliometric analysis of these six SIMs, this study identifies three patterns: field integration, niche creation, and disruptive insurgence. Field integration SIMs such as evidence-based medicine and translational medicine are characterized by centrality of key concept papers of the SIM in co-citation networks and dense institutional and country collaboration networks, signaling the resonance of the SIM to the broader biomedical community. In contrast, niche creation SIMs such as stratified medicine and genomic medicine are characterized by lower levels of annual scientific production, the lack centrality or connectivity of key concept papers in co-citation networks, and less density in collaboration networks. Disruptive insurgence SIMs such as precision medicine and personalized medicine are characterized by a high level of annual scientific production, driven by a smaller core of institutions and countries. This is likely a transitional stage as field disrupting SIMs can either become integrated with the broader field or become influential in niches. Proponents of the current push for precision medicine should ensure that a wide range of institutions and specialties be included while being mindful of the dominance of cancer and genomic approaches to health and medicine., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The rapid evolution and wide applicability of genomic testing means that medical practitioners outside the field are not appropriately skilled to understand the utility of genomics for their patients. Rotating junior doctors through genomic medicine provides them with the hands-on experience necessary to understand the complexities in this field. In this study, we analysed the training experience of 12 hospital medical officers who rotated through genomic medicine at the Royal Melbourne Hospital. Here, we demonstrate that immersion in clinical genomics aids in mainstreaming genomics knowledge., (© 2021 Royal Australasian College of Physicians.)

Background and Aim: Mapping the power, interest, and stance of stakeholders is a cornerstone for genomic medicine implementation. In this study, we aimed at mapping the power/interest of various stakeholders in United Arab Emirates (UAE) and exploring their attitudes toward pressing health genomics aspects. The overarching aim of this study is to facilitate the construction of a road map for the full implementation of genomic medicine and pharmacogenomics in the UAE with potential applicability to many healthcare systems around the world., Methods: A qualitative approach using in-depth interview was employed. Heterogeneous stakeholders were identified by experts in the field. The analysis of the data was a hybrid of deductive and inductive approach using NVivo software for coding and analysis., Results: 13 interviews were conducted. Following mapping the Mendelow's matrix, we categorized the stakeholders in UAE to promoter, latent, defender, and apathetic. Most of the interviewed stakeholders emphasized the clinical demand for genomic medicine in UAE. However, many of them were less inclined to articulate the need for pharmacogenomics at the moment. The majority of stakeholders in UAE were in favor of building infrastructure for better genetic services in the country. Stakeholder from an insurance sector had contradicting stance about the cost-effectiveness of genomic medicine; the majority were concerned with the legal and ethical aspects of genomic medicine and had an opposing stance on direct-to-consumer kits., Conclusions: Implementing the Mendelow's model will allow the systematic strategy for implementing genomic medicine in UAE. This can be achieved by engaging the key players (promoters and defenders) as well as engaging and satisfying the latent stakeholder., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

In the post-genomic era, genomic medicine interventions as a key component of personalized medicine and tailored-made health care are greatly anticipated following recent scientific and technological advances. Indeed, large-scale sequencing efforts that explore human genomic variation have been initiated in several, mostly developed, countries across the globe, such as the United States, the United Kingdom, and a few others. Here, we highlight the successful implementation of large-scale national genomic initiatives, namely the Genome of Greece (GoGreece) and the DNA do Brasil (DNABr), aiming to emphasize the importance of implementing such initiatives in developing countries. Based on this experience, we also provide a roadmap for replicating these projects in other low-resource settings, thereby bringing genomic medicine in these countries closer to clinical fruition., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The development of specialized training programs for medical personnel, particularly nurses, clinical laboratory technicians, and pharmacists, is considered critical for the promotion of genomic medicine throughout Japan. Specifically, medical personnel skilled at analyzing and understanding high-throughput genomic data are in high demand. In this symposium, we will introduce the basic knowledge and skills necessary for processing genomic data.

Since September of 2017, the Department of Pharmacy at Keio University Hospital has participated in activities of the A-3 Group in the "Program for Promoting a Platform of Genomics-based Drug Discovery" conducted by the Japan Agency for Medical Research and Development (AMED). The A-3 Group works to develop programs for fostering human resources in genomic medicine in order to solve various problems, and the Keio Department of Pharmacy plans and holds twice-yearly seminars for pharmacists interested in genomic medicine. In this review, we give an overview of efforts toward the development of pharmacists involved in genomic medicine, and we present the results of questionnaires about previous seminars.

Defects in pre-mRNA splicing are frequently a cause of Mendelian disease. Despite the advent of next-generation sequencing, allowing a deeper insight into a patient's variant landscape, the ability to characterize variants causing splicing defects has not progressed with the same speed. To address this, recent years have seen a sharp spike in the number of splice prediction tools leveraging machine learning approaches, leaving clinical geneticists with a plethora of choices for in silico analysis. In this review, some basic principles of machine learning are introduced in the context of genomics and splicing analysis. A critical comparative approach is then used to describe seven recent machine learning-based splice prediction tools, revealing highly diverse approaches and common caveats. We find that, although great progress has been made in producing specific and sensitive tools, there is still much scope for personalized approaches to prediction of variant impact on splicing. Such approaches may increase diagnostic yields and underpin improvements to patient care.

Rapid advances in genomic technologies combined with drastic reductions in cost and a growing number of clinical genomic tests are transforming medical practice. While enthusiasm about applications of precision medicine is high, the existing clinical genetics workforce is insufficient to meet present demands and will fall increasingly short as the use of genetic and genomic testing becomes more routine. To address this shortage, physicians in all areas of medicine will require genomic literacy. Undergraduate medical students, therefore, need a solid foundation in genetics and genomics so they can apply genomic medicine across a range of specialties. Here, we review the current trends and challenges in undergraduate medical genetics education in North America, highlight innovations and offer recommendations.

The Clinical Genome Resource (ClinGen) is supported by the National Institutes of Health (NIH) to develop expertly curated and freely accessible resources defining the clinical relevance of genes and variants for use in precision medicine and research. To facilitate expert input, ClinGen has formed Clinical Domain Working Groups (CDWGs) to leverage the collective knowledge of clinicians, laboratory diagnosticians, and researchers. In the initial phase of ClinGen, CDWGs were launched in the cardiovascular, hereditary cancer, and inborn errors of metabolism clinical fields. These early CDWGs established the infrastructure necessary to implement standardized processes developed or adopted by ClinGen working groups for the interpretation of gene-disease associations and variant pathogenicity, and provided a sustainable model for the formation of future disease-focused curation groups. The establishment of CDWGs requires recruitment of international experts to broadly represent the interests of their field and ensure that assertions made are reliable and widely accepted. Building on the successes, challenges, and trade-offs made in establishing the original CDWGs, ClinGen has developed standard operating procedures for the development of CDWGs in new clinical domains, while maximizing efforts to scale up curation and facilitate involvement of external groups who wish to utilize ClinGen methods and infrastructure for expert curation.

Clinical genetics in the 21st century is associated with the prevention, prediction, therapeutic and reproductive application of genomics. Its basis is the determination of the individual germinal genome and the monitoring of dynamic and tissue-specific regulation of its activity (epigenomics, transcriptomics) and translation (proteomics, metabolomics) influenced by acquired somatic mutations and environment. This "multi-omic" approach is the basis for both population preventive programs and precise medicine, allowing individual preventive and therapeutic approaches. In addition to preventive information (including the prevention of transmission of clinically relevant variants by preimplantation and prenatal diagnostics or genome editing) and use in precision treatment, genomic information may have a fatal impact on life. While the requirements of erudition are fundamentally altered, the principles of genetic counselling must always be respected: non-directiveness, respecting the right to refuse information and preserving medical secret.

The potential of genomics to improve health comes with the peril that the benefits will not be equitably available to all populations. Existing health disparities can be exacerbated if the implementation of genomic medicine does not intentionally focus on health equity. Defining what health equity means in the context of genomics and outlining how it can be achieved is important for the future of the field. Strategies to improve health equity include addressing underrepresentation of diverse populations in genomic research, investigating how genomic services can be deployed in diverse health care settings and underserved communities, increasing workforce diversity, supporting infrastructure development outside traditional research centers, and engaging communities and health care providers. By employing these strategies, the genomic research community can advance health equity in genomic medicine., Competing Interests: Competing Interests: None declared.

Health care delivery is increasingly influenced by the emerging concepts of precision health and the learning health care system. Although not synonymous with precision health, genomics is a key enabler of individualized care. Delivering patient-centered, genomics-informed care based on individual-level data in the current national landscape of health care delivery is a daunting challenge. Problems to overcome include data generation, analysis, storage, and transfer; knowledge management and representation for patients and providers at the point of care; process management; and outcomes definition, collection, and analysis. Development, testing, and implementation of a genomics-informed program requires multidisciplinary collaboration and building the concepts of precision health into a multilevel implementation framework. Using the principles of a learning health care system provides a promising solution. This article describes the implementation of population-based genomic medicine in an integrated learning health care system-a working example of a precision health program.

Precision medicine is making an impact on patients, health care delivery systems, and research participants in ways that were only imagined fifteen years ago when the human genome was first sequenced. Discovery of disease-causing and drug-response genetic variants has accelerated, while adoption into clinical medicine has lagged. We define precision medicine and the stakeholder community required to enable its integration into research and health care. We explore the intersection of data science, analytics, and precision medicine in the formation of health systems that carry out research in the context of clinical care and that optimize the tools and information used to deliver improved patient outcomes. We provide examples of real-world impact and conclude with a policy and economic agenda necessary for the adoption of this new paradigm of health care both in the United States and globally.

Background: Increasing affordability of next-generation sequencing (NGS) has created an opportunity for realizing genomically-informed personalized cancer therapy as a path to precision oncology. However, the complex nature of genomic information presents a huge challenge for clinicians in interpreting the patient's genomic alterations and selecting the optimum approved or investigational therapy. An elaborate and practical information system is urgently needed to support clinical decision as well as to test clinical hypotheses quickly., Results: Here, we present an integrated clinical and genomic information system (CGIS) based on NGS data analyses. Major components include modules for handling clinical data, NGS data processing, variant annotation and prioritization, drug-target-pathway analysis, and population cohort explorer. We built a comprehensive knowledgebase of genes, variants, drugs by collecting annotated information from public and in-house resources. Structured reports for molecular pathology are generated using standardized terminology in order to help clinicians interpret genomic variants and utilize them for targeted cancer therapy. We also implemented many features useful for testing hypotheses to develop prognostic markers from mutation and gene expression data., Conclusions: Our CGIS software is an attempt to provide useful information for both clinicians and scientists who want to explore genomic information for precision oncology.

Clinical medicine of the future is poised to use an individual's genomic data to predict disease risk and guide clinical care. The treatment of cigarette smoking and tobacco use disorder represents a prime area for genomics implementation. The genes CHRNA5 and CYP2A6 are strong genomic contributors that alter the risk of heaviness of smoking, tobacco use disorder, and smoking-related diseases in humans. These biomarkers have proven analytical and clinical validity, and evidence for their clinical utility continues to grow. We propose that these biomarkers harbor the potential of enabling the identification of elevated disease risk in smokers, personalizing smoking cessation treatments, and motivating behavioral changes. We must prepare for the integration of genomic applications into clinical care of patients who smoke., (Copyright © 2017 Elsevier Ltd. All rights reserved.)