Maureen E. Smith

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

The Clinical Genome Resource (ClinGen) Consent and Disclosure Recommendation (CADRe) framework proposes that key components of informed consent for genetic testing can be covered with a targeted discussion for many conditions rather than a time-intensive traditional genetic counseling approach. We surveyed US genetics professionals (medical geneticists and genetic counselors) on their response to scenarios that proposed core informed consent concepts for clinical genetic testing developed in a prior expert consensus process. The anonymous online survey included responses to 3 (of 6 possible) different clinical scenarios that summarized the application of the core concepts. There was a binary (yes/no) question asking respondents whether they agreed the scenarios included the minimum necessary and critical educational concepts to allow an informed decision. Respondents then provided open-ended feedback on what concepts were missing or could be removed. At least one scenario was completed by 238 respondents. For all but one scenario, over 65% of respondents agreed that the identified concepts portrayed were sufficient for an informed decision; the exome scenario had the lowest agreement (58%). Qualitative analysis of the open-ended comments showed no consistently mentioned concepts to add or remove. The level of agreement with the example scenarios suggests that the minimum critical educational components for pre-test informed consent proposed in our prior work is a reasonable starting place for targeted pre-test discussions. This may be helpful in providing consistency to the clinical practice of both genetics and non-genetics providers, meeting patients’ informational needs, tailoring consent for psychosocial support, and in future guideline development.

Purpose: Informed consent for genetic testing has historically been acquired during pretest genetic counseling, without specific guidance defining which core concepts are required. Methods: The Clinical Genome Resource (ClinGen) Consent and Disclosure Recommendations Workgroup (CADRe) used an expert consensus process to identify the core concepts essential to consent for clinical genetic testing. A literature review identified 77 concepts that are included in informed consent for genetic tests. Twenty-five experts (9 medical geneticists, 8 genetic counselors, and 9 bioethicists) completed two rounds of surveys ranking concepts’ importance to informed consent. Results: The most highly ranked concepts included: (1) genetic testing is voluntary; (2) why is the test recommended and what does it test for?; (3) what results will be returned and to whom?; (4) are there other types of potential results, and what choices exist?; (5) how will the prognosis and management be impacted by results?; (6) what is the potential family impact?; (7) what are the test limitations and next steps?; and (8) potential risk of genetic discrimination and legal protections. Conclusion: Defining the core concepts necessary for informed consent for genetic testing provides a foundation for quality patient care across a variety of healthcare providers and clinical indications.

Some individuals’ understanding of informed consent (IC) information may improve with electronic delivery, but others may benefit from face-to-face (F2F). This randomized, multisite study explores how individuals from diverse backgrounds understand electronic IC documents versus F2F, their confidence in understanding, and enrollment in research. A total of 501 patients at two U.S. biobanks with diverse populations participated. There were no overall differences between electronic and F2F understanding, but F2F predicted higher confidence in understanding and enrollment. Ethnicity and a higher educational level predicted higher understanding and confidence. Study findings suggest that electronic consent may lead to better understanding for non-Hispanic patients of higher socioeconomic status. F2F processes may lead to better understanding and higher enrollment of patients from Hispanic and lower socioeconomic levels. Researchers should carefully consider how they implement electronic IC processes and whether to maintain an F2F process to better address the needs and limitations of some populations.

Unbiased estimates of penetrance are challenging but critically important to make informed choices about strategies for risk management through increased surveillance and risk-reducing interventions. We studied the penetrance and clinical outcomes of 7 breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2, and PTEN) in almost 13 458 participants unselected for personal or family history of breast cancer. We identified 242 female participants with pathogenic or likely pathogenic variants in 1 of the 7 genes for penetrance analyses, and 147 women did not previously know their genetic results. Out of the 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 17.8% to 43.8%, depending on the gene. In clinical-impact analysis, 42.3% (95% confidence interval = 31.3% to 53.3%) of women had taken actions related to their genetic results, and 2 new breast cancer cases were identified within the first 12 months after genetic results disclosure. Our study provides population-based penetrance estimates for the understudied genes CHEK2, ATM, and PALB2 and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve health care through early diagnosis and preventative screening.

Increasing interest and pursuit of genetic testing by the general public have raised concerns about their understanding and use of their results. While most research has focused on individuals receiving positive genetic test results, there have been limited investigations assessing the understanding and utility of receiving negative genetic test results. Individuals who receive a negative (or uninformative) genetic test result may not appreciate the limitations of genetic testing and their residual disease risk. The goals of this study were to explore participant understanding and perceived utility of negative non‐diagnostic genetic test results. We conducted semi‐structured interviews with participants who received negative non‐diagnostic genetic test results from the electronic Medical Records and Genomics Network (eMERGE) testing panel at Northwestern University. A total of 17 participants were interviewed. While many expressed a lack of understanding of genetics and the relationship between genes, disease, and environment, most acknowledged that they had residual risk to develop a health problem and should continue with their routine health management. Additionally, participants expressed that their negative results had personal value, by providing them peace of mind and learning additional knowledge about themselves and their health. Participants did not anticipate that results would have an impact on their lifestyle, but felt the results were useful for sharing with their physician and could inform future genetic testing decisions. While mostly positive, some participants were disappointed not to learn more individualized results. While a more thorough exploration is necessary, findings in this study can aid efforts to improve or innovate informed consent for genomic testing, as well as scalable modes of result return that foster comprehension following negative genetic testing.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the “real world” of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.

From a public health perspective, the “All of Us” study provides an opportunity to isolate targeted and cost-effective prevention and early-detection strategies. Identifying motivations for participation in large-scale genomic sequencing (LSGS) studies, and motivations and preferences to receive results will help determine effective strategies for “All of Us” study implementation. This paper offers a critical review of the literature regarding LSGS for adult onset hereditary conditions where results could indicate an increased risk to develop disease. The purpose of this review is to synthesize studies which explored peoples’ motivations for participating in LSGS studies, and their desire to receive different types of genetic results. Participants were primarily motivated by altruism, desire to know more about their health, and curiosity. When asked about hypothetically receiving results, most participants in hypothetical studies wanted all results except those which were uncertain (i.e., a variant of uncertain significance (VUS)). However, participants in studies where results were returned preferred to receive only results for which an intervention was available, but also wanted VUS. Concerns about peoples’ understanding of results and possible psychosocial implications are noted. Most studies examined populations classified as “early adopters,” therefore, additional research on motivations and expectations among the general public, minority, and underserved populations is needed.