Clinical genetic counseling and translation considerations for polygenic scores in personalized risk assessments: A Practice Resource from the National Society of Genetic Counselors.

Polygenic scores (PGS) are primed for use in personalized risk assessments for common, complex conditions and population health screening. Although there is growing evidence supporting the clinical validity of these scores in certain diseases, presently, there is no consensus on best practices for constructing PGS or demonstrated clinical utility in practice. Despite these evidence gaps, individuals can access their PGS information through commercial entities, research programs, and clinical programs. This prompts the immediate need for educational resources for clinicians encountering PGS information in clinical practice. This practice resource is intended to increase genetic counselors' and other healthcare providers' understanding and comfort with PGS used in personalized risk assessments. Drawing on best practices in clinical genomics, we discuss the unique considerations for polygenic-based (1) testing, (2) clinical genetic counseling, and (3) translation to population health services. This practice resource outlines the emerging uses of PGS, as well as the critical limitations of this technology that need to be addressed before wide-scale implementation.

Secondary findings: How did we get here, and where are we going?

The American College of Medical Genetics and Genomics (ACMG) recommendations for reporting of incidental (now "secondary") findings in clinical exome and genome sequencing (Green et al., Genet Med 15:565, 2013) is an often cited and sometimes misapplied professional guideline. To best approach the current state of secondary findings (SFs) in genomic medicine, and consider their impact, it is helpful to understand how and why the guideline was created. Of particular importance is the context - the state of the science and clinical practice during 2011-2012 when the guideline were initially developed. This paper will review the setting before the guidelines were published, and empiric research and discussion that has occurred since.

Social comparisons and quality of life following a prostate cancer diagnosis.

PURPOSE: The objective was to explore the relationships among cognitive appraisals of prostate cancer (challenge, threat, and harm/loss), social comparisons, and quality of life in men previously diagnosed. Design, Sample, & Methods: Men who had participated in prostate cancer support groups completed a cross-sectional questionnaire (N = 189). Multivariable linear regression was used to evaluate social comparisons as mediators of quality of life while controlling for uncertainty and optimism. FINDINGS: Positive and negative social comparisons were parallel mediators of the relationships between challenge or threat appraisals and quality of life, while only negative social comparisons mediated the relationship between harm/loss appraisals and quality of life. CONCLUSIONS: These findings demonstrate the importance of social comparisons in accounting for the effect of cognitive appraisals of prostate cancer on quality of life among men in support groups. Implications for Psychosocial Providers: Interventions to improve quality of life could address reduction of maladaptive comparisons, a strategy that could be tailored based on the patient's appraisal of prostate cancer.

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical services. Adherence to these recommendations is completely voluntary and does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.To promote standardized reporting of actionable information from clinical genomic sequencing, in 2013, the American College of Medical Genetics and Genomics (ACMG) published a minimum list of genes to be reported as incidental or secondary findings. The goal was to identify and manage risks for selected highly penetrant genetic disorders through established interventions aimed at preventing or significantly reducing morbidity and mortality. The ACMG subsequently established the Secondary Findings Maintenance Working Group to develop a process for curating and updating the list over time. We describe here the new process for accepting and evaluating nominations for updates to the secondary findings list. We also report outcomes from six nominations received in the initial 15 months after the process was implemented. Applying the new process while upholding the core principles of the original policy statement resulted in the addition of four genes and removal of one gene; one gene did not meet criteria for inclusion. The updated secondary findings minimum list includes 59 medically actionable genes recommended for return in clinical genomic sequencing. We discuss future areas of focus, encourage continued input from the medical community, and call for research on the impact of returning genomic secondary findings.Genet Med 19 2, 249-255.

Parents are interested in newborn genomic testing during the early postpartum period.

PURPOSE: We surveyed parents to ascertain interest in newborn genomic testing and determine whether these queries would provoke refusal of conventional state-mandated newborn screening. METHODS: After a brief genetics orientation, parents rated their interest in receiving genomic testing for their healthy newborn on a 5-point Likert scale and answered questions about demographics and health history. We used logistic regression to explore factors associated with interest in genomic testing and tracked any subsequent rejection of newborn screening. RESULTS: We queried 514 parents within 48 hours after birth while still in hospital (mean age (SD) 32.7 (6.4) years, 65.2% female, 61.2% white, 79.3% married). Parents reported being not at all (6.4%), a little (10.9%), somewhat (36.6%), very (28.0%), or extremely (18.1%) interested in genomic testing for their newborns. None refused state-mandated newborn screening. Married participants and those with health concerns about their infant were less interested in newborn genomic testing (P = 0.012 and P = 0.030, respectively). Degree of interest for mothers and fathers was discordant (at least two categories different) for 24.4% of couples. CONCLUSION: Interest in newborn genomic testing was high among parents of healthy newborns, and the majority of couples had similar levels of interest. Surveying parents about genomic sequencing did not prompt rejection of newborn screening.Genet Med 17 6, 501-504.

Development of a breast cancer risk prediction model integrating monogenic, polygenic, and epidemiologic risk.

BACKGROUND: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited. METHODS: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium. RESULTS: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population. CONCLUSIONS: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification. IMPACT: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.

ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the "normal" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.

Effect of communicating personalized rheumatoid arthritis risk on concern for developing RA: A randomized controlled trial.

OBJECTIVE: To investigate the effect of providing comprehensive personalized risk information on concern for chronic disease development. METHODS: Unaffected first-degree relatives (FDRs) of rheumatoid arthritis (RA) patients (n = 238) were randomly allocated to: 1) disclosure of RA risk personalized to demographics, genetics, biomarkers, and behaviors using a web-based tool (PRE-RA arm, n = 78); 2) PRE-RA with interpretation by a health educator (PRE-RA Plus arm, n = 80); and 3) standard RA education (Comparison arm, n = 80). Concern for developing RA was assessed at baseline and immediately, 6 weeks, 6 months, and 12 months post-intervention. RESULTS: FDRs randomized to PRE-RA arms were less concerned about developing RA than the Comparison arm at all post-intervention assessments (p < 0.05). Among those concerned about RA risk at baseline, the PRE-RA (OR = 4.7, 95%CI 1.5-14.4) and PRE-RA Plus (OR = 5.2, 95%CI 1.6-17.3) arms were more likely to have reassurance 6 months post-intervention than the Comparison arm. CONCLUSION: A comprehensive tool provided reassurance to those at risk for developing a chronic disease, with or without interpretation from a health educator, compared to standard education. PRACTICE IMPLICATIONS: Individuals may be more likely to be reassured using a personalized chronic disease risk disclosure tool than a standard non-personalized approach.

Effectiveness of a Web-Based Personalized Rheumatoid Arthritis Risk Tool With or Without a Health Educator for Knowledge of Rheumatoid Arthritis Risk Factors.

OBJECTIVE: To assess knowledge of rheumatoid arthritis (RA) risk factors among unaffected first-degree relatives (FDRs) and to study whether a personalized RA education tool increases risk factor knowledge. METHODS: We performed a randomized controlled trial assessing RA educational interventions among 238 FDRs. The web-based Personalized Risk Estimator for RA (PRE-RA) tool displayed personalized RA risk results (genetics, autoantibodies, demographics, and behaviors) and educated about risk factors. Subjects were randomly assigned to a Comparison arm (standard RA education; n = 80), a PRE-RA arm (PRE-RA alone; n = 78), or a PRE-RA Plus arm (PRE-RA and a one-on-one session with a trained health educator; n = 80). The RA Knowledge Score (RAKS), the number of 8 established RA risk factors identified as related to RA, was calculated at baseline and post-education (immediate/6 weeks/6 months/12 months). We compared RAKS and its components at each post-education point by randomization arm. RESULTS: At baseline before education, few FDRs identified behavioral RA risk factors (15.6% for dental health, 31.9% for smoking, 47.5% for overweight/obesity, and 54.2% for diet). After education, RAKS increased in all arms, higher in PRE-RA and PRE-RA Plus than Comparison at all post-education points (P < 0.05). PRE-RA subjects were more likely to identify risk factors than those who received standard education (proportion agreeing that smoking is a risk factor at 6 weeks: 83.1% in the PRE-RA Plus arm, 71.8% in the PRE-RA arm, and 43.1% in the Comparison arm; P < 0.05 for PRE-RA versus Comparison). CONCLUSION: Despite being both familiar with RA and at increased risk, FDRs had low knowledge about RA risk factors. A web-based personalized RA education tool successfully increased RA risk factor knowledge.

Disclosure of Personalized Rheumatoid Arthritis Risk Using Genetics, Biomarkers, and Lifestyle Factors to Motivate Health Behavior Improvements: A Randomized Controlled Trial.

OBJECTIVE: To determine the effect of disclosure of rheumatoid arthritis (RA) risk personalized with genetics, biomarkers, and lifestyle factors on health behavior intentions. METHODS: We performed a randomized controlled trial among first-degree relatives without RA. Subjects assigned to the Personalized Risk Estimator for Rheumatoid Arthritis (PRE-RA) group received the web-based PRE-RA tool for RA risk factor education and disclosure of personalized RA risk estimates, including genotype/autoantibody results and behaviors (n = 158). Subjects assigned to the comparison arm received standard RA education (n = 80). The primary outcome was readiness for change based on the trans-theoretical model, using validated contemplation ladder scales. Increased motivation to improve RA risk-related behaviors (smoking, diet, exercise, or dental hygiene) was defined as an increase in any ladder score compared to baseline, assessed immediately, 6 weeks, and 6 months post-intervention. Subjects reported behavior change at each visit. We performed intent-to-treat analyses using generalized estimating equations for the binary outcome. RESULTS: Subjects randomized to PRE-RA were more likely to increase ladder scores over post-intervention assessments (relative risk 1.23, 95% confidence interval [95% CI] 1.01, 1.51) than those randomized to nonpersonalized education. At 6 months, 63.9% of PRE-RA subjects and 50.0% of comparison subjects increased motivation to improve behaviors (age-adjusted difference 15.8%; 95% CI 2.8%, 28.8%). Compared to nonpersonalized education, more PRE-RA subjects increased fish intake (45.0% versus 22.1%; P = 0.005), brushed more frequently (40.7% versus 22.9%; P = 0.01), flossed more frequently (55.7% versus 34.8%; P = 0.004), and quit smoking (62.5% versus 0.0% among 11 smokers; P = 0.18). CONCLUSION: Disclosure of RA risk personalized with genotype/biomarker results and behaviors increased motivation to improve RA risk-related behaviors. Personalized medicine approaches may motivate health behavior improvements for those at risk for RA and provide rationale for larger studies evaluating effects of behavior changes on clinical outcomes, such as RA-related autoantibody production or RA development.

Personal Genomic Testing for Cancer Risk: Results From the Impact of Personal Genomics Study.

Purpose Significant concerns exist regarding the potential for unwarranted behavior changes and the overuse of health care resources in response to direct-to-consumer personal genomic testing (PGT). However, little is known about customers' behaviors after PGT. Methods Longitudinal surveys were given to new customers of 23andMe (Mountain View, CA) and Pathway Genomics (San Diego, CA). Survey data were linked to individual-level PGT results through a secure data transfer process. Results Of the 1,042 customers who completed baseline and 6-month surveys (response rate, 71.2%), 762 had complete cancer-related data and were analyzed. Most customers reported that learning about their genetic risk of cancers was a motivation for testing (colorectal, 88%; prostate, 95%; breast, 94%). No customers tested positive for pathogenic mutations in highly penetrant cancer susceptibility genes. A minority of individuals received elevated single nucleotide polymorphism-based PGT cancer risk estimates (colorectal, 24%; prostate, 24%; breast, 12%). At 6 months, customers who received elevated PGT cancer risk estimates were not significantly more likely to change their diet, exercise, or advanced planning behaviors or engage in cancer screening, compared with individuals at average or reduced risk. Men who received elevated PGT prostate cancer risk estimates changed their vitamin and supplement use more than those at average or reduced risk (22% v 7.6%, respectively; adjusted odds ratio, 3.41; 95% CI, 1.44 to 8.18). Predictors of 6-month behavior include baseline behavior (exercise, vitamin or supplement use, and screening), worse health status (diet and vitamin or supplement use), and older age (advanced planning, screening). Conclusion Most adults receiving elevated direct-to-consumer PGT single nucleotide polymorphism-based cancer risk estimates did not significantly change their diet, exercise, advanced care planning, or cancer screening behaviors.

Genomic sequencing in clinical practice: applications, challenges, and opportunities.

The development of massively parallel sequencing (or next-generation sequencing) has facilitated a rapid implementation of genomic sequencing in clinical medicine. Genomic sequencing (GS) is now an essential tool for evaluating rare disorders, identifying therapeutic targets in neoplasms, and screening for prenatal aneuploidy. Emerging applications, such as GS for preconception carrier screening and predisposition screening in healthy individuals, are being explored in research settings and utilized by members of the public eager to incorporate genomic information into their health management. The rapid pace of adoption has created challenges for all stakeholders in clinical GS, from standardizing variant interpretation approaches in clinical molecular laboratories to ensuring that nongeneticist clinicians are prepared for new types of clinical information. Clinical GS faces a pivotal moment, as the vast potential of new quantities and types of data enable further clinical innovation and complicated implementation questions continue to be resolved.

El desarrollo masivo de la secuenciación paralela o de nueva generación ha facilitado una rápida implementación de la secuenciación genómica en la medicina clínica. Hoy en día la secuenciación genómica (SG) es una herramienta esencial para evaluar trastornos raros, identificar blancos terapéuticos en neoplasias y evaluar la aneuploidía prenatal. Las aplicaciones emergentes, como la SG para el tamizaje antes de la concepción de portadores y la evaluación de predisposiciones en sujetos sanos están siendo exploradas en ambientes de investigación y empleadas por miembros de un público ávido de la incorporación de la información genómica para su atención de salud. El rápido ritmo de adopción ha creado desafíos para todos los interesados en la SG clínica, desde los enfoques centrados en la interpretación de variantes estandarizadas en laboratorios moleculares clínicos hasta asegurar que los clínicos no genetistas estén preparados para nuevos tipos de información clínica. La SG clínica se enfrenta a un momento crucial, ya que el gran potencial de nuevas cantidades y tipos de datos posibilitan una mayor innovación clínica mientras continúa la resolución de las preguntas acerca de la complicada implementación.

La mise en place rapide du séquençage génomique en médecine clinique a été facilitée par le développement d'un séquençage massivement parallèle (ou séquençage de deuxième génération). Le séquençage génomique (SG) est maintenant un outil essentiel pour l'évaluation des maladies rares, l'identification des cibles thérapeutiques dans les cancers et le dépistage de l'aneuploïdie prénatale. Les applications naissantes comme le SG pour le test de dépistage du statut de porteur sain d'une anomalie avant la conception d'un enfant et le test de prédisposition génétique pour les sujets sains, font l'objet de recherches et sont utilisées par des usagers soucieux d'inclure l'information génomique dans la prise en charge de leur santé. De par cette adoption rapide, tous les acteurs du SG clinique ont été confrontés à des difficultés allant de la standardisation de différentes approches dans l'interprétation des résultats dans les laboratoires de diagnostic moléculaire à l'assurance de la préparation des médecins non généticiens pour recevoir ces nouvelles formes d'information. Le séquençage génomique est à une phase cruciale compte tenu de l'énorme potentiel des nouveautés dans la quantité et le type de données pouvant déboucher sur de futures innovations cliniques ; des problèmes de mise en ?uvre complexe sont encore à résoudre.

Explaining, not just predicting, drives interest in personal genomics.

BACKGROUND: There is a widespread assumption that risk prediction is the major driver of customer interest in personal genomic testing (PGT). However, some customers may also be motivated by finding out whether their existing diseases have a genetic etiology. We evaluated the impact of an existing medical diagnosis on customer interest in condition-specific results from PGT. METHODS: Using a prospective online survey of PGT customers, we measured customer interest prior to receiving PGT results for 11 health conditions, and examined the association between interest and personal medical history of these conditions using logistic regression. RESULTS: We analyzed data from 1,538 PGT customers, mean age 48.7 years, 61 % women, 90 % White, and 47 % college educated. The proportion of customers who were 'very interested' in condition-specific PGT varied considerably, from 28 % for ulcerative colitis to 68% for heart disease. After adjusting for demographic and personal characteristics including family history, having a diagnosis of the condition itself was significantly associated with interest in genetic testing for risk of that condition, with odds ratios ranging from 2.07 (95 % CI 1.28-3.37) for diabetes to 19.99 (95 % CI 4.57-87.35) for multiple sclerosis. CONCLUSIONS: PGT customers are particularly interested in genetic markers for their existing medical conditions, suggesting that the value of genetic testing is not only predictive, but also explanatory.

How Well Do Customers of Direct-to-Consumer Personal Genomic Testing Services Comprehend Genetic Test Results? Findings from the Impact of Personal Genomics Study.

AIM: To assess customer comprehension of health-related personal genomic testing (PGT) results. METHODS: We presented sample reports of genetic results and examined responses to comprehension questions in 1,030 PGT customers (mean age: 46.7 years; 59.9% female; 79.0% college graduates; 14.9% non-White; 4.7% of Hispanic/Latino ethnicity). Sample reports presented a genetic risk for Alzheimer's disease and type 2 diabetes, carrier screening summary results for >30 conditions, results for phenylketonuria and cystic fibrosis, and drug response results for a statin drug. Logistic regression was used to identify correlates of participant comprehension. RESULTS: Participants exhibited high overall comprehension (mean score: 79.1% correct). The highest comprehension (range: 81.1-97.4% correct) was observed in the statin drug response and carrier screening summary results, and lower comprehension (range: 63.6-74.8% correct) on specific carrier screening results. Higher levels of numeracy, genetic knowledge, and education were significantly associated with greater comprehension. Older age (≥ 60 years) was associated with lower comprehension scores. CONCLUSIONS: Most customers accurately interpreted the health implications of PGT results; however, comprehension varied by demographic characteristics, numeracy and genetic knowledge, and types and format of the genetic information presented. Results suggest a need to tailor the presentation of PGT results by test type and customer characteristics.

Design, methods, and participant characteristics of the Impact of Personal Genomics (PGen) Study, a prospective cohort study of direct-to-consumer personal genomic testing customers.

Designed in collaboration with 23andMe and Pathway Genomics, the Impact of Personal Genomics (PGen) Study serves as a model for academic-industry partnership and provides a longitudinal dataset for studying psychosocial, behavioral, and health outcomes related to direct-to-consumer personal genomic testing (PGT). Web-based surveys administered at three time points, and linked to individual-level PGT results, provide data on 1,464 PGT customers, of which 71% completed each follow-up survey and 64% completed all three surveys. The cohort includes 15.7% individuals of non-white ethnicity, and encompasses a range of income, education, and health levels. Over 90% of participants agreed to re-contact for future research.

Personalized Risk Estimator for Rheumatoid Arthritis (PRE-RA) Family Study: rationale and design for a randomized controlled trial evaluating rheumatoid arthritis risk education to first-degree relatives.

We present the rationale, design features, and protocol of the Personalized Risk Estimator for Rheumatoid Arthritis (PRE-RA) Family Study (ClinicalTrials.gov NCT02046005). The PRE-RA Family Study is an NIH-funded prospective, randomized controlled trial designed to compare the willingness to change behaviors in first-degree relatives of rheumatoid arthritis (RA) patients without RA after exposure to RA risk educational programs. Consented subjects are randomized to receive education concerning their personalized RA risk based on demographics, RA-associated behaviors, genetics, and biomarkers or to receive standard RA information. Four behavioral factors associated with RA risk were identified from prior studies for inclusion in the risk estimate: cigarette smoking, excess body weight, poor oral health, and low fish intake. Personalized RA risk information is presented through an online tool that collects data on an individual's specific age, gender, family history, and risk-related behaviors; presents genetic and biomarker results; displays relative and absolute risk of RA; and provides personalized feedback and education. The trial outcomes will be changes in willingness to alter behaviors from baseline to 6 weeks, 6 months, and 12 months in the three intervention groups. The design and the execution of this trial that targets a special population at risk for RA, while incorporating varied risk factors into a single risk tool, offer distinct challenges. We provide the theoretical rationale for the PRE-RA Family Study and highlight particular design features of this trial that utilize personalized risk education as an intervention.