Polygenic risk score as a possible tool for identifying familial monogenic causes of complex diseases

PurposeThe study aimed to evaluate whether polygenic risk scores could be helpful in addition to family history for triaging individuals to undergo deep-depth diagnostic sequencing for identifying monogenic causes of complex diseases.MethodsAmong 44,550 exome-sequenced European ancestry UK Biobank participants, we identified individuals with a clinically reported or computationally predicted monogenic pathogenic variant for breast cancer, bowel cancer, heart disease, diabetes, or Alzheimer disease. We derived polygenic risk scores for these diseases. We tested whether a polygenic risk score could identify rare pathogenic variant heterozygotes among individuals with a parental disease history.ResultsMonogenic causes of complex diseases were more prevalent among individuals with a parental disease history than in the rest of the population. Polygenic risk scores showed moderate discriminative power to identify familial monogenic causes. For instance, we showed that prescreening the patients with a polygenic risk score for type 2 diabetes can prioritize individuals to undergo diagnostic sequencing for monogenic diabetes variants and reduce needs for such sequencing by up to 37%.ConclusionAmong individuals with a family history of complex diseases, those with a low polygenic risk score are more likely to have monogenic causes of the disease and could be prioritized to undergo genetic testing.     

Family history and the natural history of colorectal cancer: systematic review

PurposeFamily history of colorectal cancer (CRC) is a known risk factor for CRC and encompasses both genetic and shared environmental risks.MethodsWe conducted a systematic review to estimate the impact of family history on the natural history of CRC and adherence to screening.ResultsWe found high heterogeneity in family-history definitions, the most common definition being one or more first-degree relatives. The prevalence of family history may be lower than the commonly cited 10%, and confirms evidence for increasing levels of risk associated with increasing family-history burden. There is evidence for higher prevalence of adenomas and of multiple adenomas in people with family history of CRC but no evidence for differential adenoma location or adenoma progression by family history. Limited data regarding the natural history of CRC by family history suggest a differential age or stage at cancer diagnosis and mixed evidence with respect to tumor location. Adherence to recommended colonoscopy screening was higher in people with a family history of CRC.ConclusionStratification based on polygenic and/or multifactorial risk assessment may mature to the point of displacing family history–based approaches, but for the foreseeable future, family history may remain a valuable clinical tool for identifying individuals at increased risk for CRC.Genet Med17 9, 702–712.     

Privacy-preserving genomic testing in the clinic: a model using HIV treatment

PurposeThe implementation of genomic-based medicine is hindered by unresolved questions regarding data privacy and delivery of interpreted results to health-care practitioners. We used DNA-based prediction of HIV-related outcomes as a model to explore critical issues in clinical genomics.MethodsWe genotyped 4,149 markers in HIV-positive individuals. Variants allowed for prediction of 17 traits relevant to HIV medical care, inference of patient ancestry, and imputation of human leukocyte antigen (HLA) types. Genetic data were processed under a privacy-preserving framework using homomorphic encryption, and clinical reports describing potentially actionable results were delivered to health-care providers.ResultsA total of 230 patients were included in the study. We demonstrated the feasibility of encrypting a large number of genetic markers, inferring patient ancestry, computing monogenic and polygenic trait risks, and reporting results under privacy-preserving conditions. The average execution time of a multimarker test on encrypted data was 865 ms on a standard computer. The proportion of tests returning potentially actionable genetic results ranged from 0 to 54%.ConclusionsThe model of implementation presented herein informs on strategies to deliver genomic test results for clinical care. Data encryption to ensure privacy helps to build patient trust, a key requirement on the road to genomic-based medicine.     

Communicating polygenic risk scores in the familial breast cancer clinic

ObjectiveTo describe the communication of polygenic risk scores (PRS) in the familial breast cancer setting.MethodsConsultations between genetic healthcare providers (GHP) and female patients who received their PRS for breast cancer risk were recorded (n = 65). GHPs included genetic counselors (n = 8) and medical practitioners (n = 5) (i.e. clinical geneticists and oncologists). A content analysis was conducted and logistic regression was used to assess differences in communication behaviors between genetic counselors (n = 8) and medical practitioners (n = 5).ResultsOf the 65 patients, 31 (47.7 %) had a personal history of breast cancer, 18 of whom received an increased PRS (relative risk >1.2). 25/34 unaffected patients received an increased PRS. Consultations were primarily clinician-driven and focused on biomedical information. There was little difference between the biomedical information provided by genetic counselors and medical practitioners. However, genetic counselors were significantly more likely to utilize strategies to build patient rapport and counseling techniques.ConclusionsOur findings provide one of the earliest reports on how breast cancer PRSs are communicated to women.Practice implicationsKey messages for communicating PRSs were identified, namely: discussing differences between polygenic and monogenic testing, the multifactorial nature of breast cancer risk, polygenic inheritance and current limitation of PRSs.     

Findings from a community education needs assessment to facilitate the integration of genomic medicine into primary care

PurposeTo assess the lay public's knowledge of, and beliefs about, genetics and genetic testing to create an educational initiative that promotes acceptance and utilization of genomic medicine in primary health care.MethodsA telephone survey of English-speaking adults in Guilford County, North Carolina was conducted in 2006 to identify community members' educational needs regarding genetics and genetic testing.ResultsMost respondents recognized the connection between family history and disease risk. A majority did not appear to know about: (1) basic principles of inheritance, (2) laws prohibiting genetic discrimination, and (3) the availability and limitations of genetic tests. About 25% thought that they could not reduce their risk if they have a genetic predisposition for disease. Knowledge level was affected by education, experience, age, and race.ConclusionIf primary care providers use family history as a risk assessment tool, community education programs must address (1) the collection of family health history, (2) legislation regarding genetic nondiscrimination, (3) benefits and limitations of existing genetic tests, and (4) genetic determinism. Programs emphasizing practical, “how to” information can be targeted to individuals likely to collect family history information and address misperceptions about discrimination, testing, and determinism.     

Potential of polygenic risk scores for improving population estimates of women’s breast cancer genetic risks

PurposeBreast cancer risk has conventionally been assessed using family history (FH) and rare high/moderate penetrance pathogenic variants (PVs), notably in BRCA1/2, and more recently PALB2, CHEK2, and ATM. In addition to these PVs, it is now possible to use increasingly predictive polygenic risk scores (PRS) as well. The comparative population-level predictive capability of these three different indicators of genetic risk for risk stratification is, however, unknown.MethodsThe Canadian heritable breast cancer risk distribution was estimated using a novel genetic mixing model (GMM). A realistically representative sample of women was synthesized based on empirically observed demographic patterns for appropriately correlated family history, inheritance of rare PVs, PRS, and residual risk from an unknown polygenotype. Risk assessment was simulated using the BOADICEA risk algorithm for 10-year absolute breast cancer incidence, and compared to heritable risks as if the overall polygene, including its measured PRS component, and PV risks were fully known.ResultsGenerally, the PRS was most predictive for identifying women at high risk, while family history was the weakest. Only the PRS identified any women at low risk of breast cancer.ConclusionPRS information would be the most important advance in enabling effective risk stratification for population-wide breast cancer screening.     

Risk estimates for complex disorders: comparing personal genome testing and family history

PurposePersonal genome testing allows the identification of single-nucleotide polymorphisms associated with an increased risk for common complex disorders. An area of concern in the use of personal genome testing is how risk estimates generated differ from traditional measures of risk (e.g., family history analysis). We sought to analyze the concordance of risk estimates generated by family history analysis and by personal genome testing.MethodsRisk categorizations for 20 complex conditions included in Navigenics personal genome testing were compared with risk categorization estimates derived from family history assessment using the kappa (κ) statistic.ResultsThe only conditions showing slight agreement between risk assessment methods were Alzheimer disease (κ = 0.131), breast cancer (κ = 0.154), and deep vein thrombosis (κ = 0.201) in females, and colon cancer (κ = 0.124) in males. Eighty-six individuals (11.4%) were found to have additional genetic risks not assessed by personal genome testing after family and medical history assessment, including 38 individuals with family histories suggestive of hereditary cancer syndromes.ConclusionDiscordance between personal genome testing and family history risk estimates suggests that these methods may provide independent information that could be used in a complementary manner. Results also support that eliciting family history adds value to overall risk assessment for individuals undergoing personal genome testing.Genet Med 2014:16(3):231–237     

Genetic risk estimation in the Coriell Personalized Medicine Collaborative

PurposeRecent genome wide-association studies have identified hundreds of single nucleotide polymorphisms associated with common complex diseases. With the momentum of these discoveries comes a need to communicate this information to individuals.MethodsThe Coriell Personalized Medicine Collaborative is an observational research study designed to evaluate the utility of personalized genomic information in health care. Participants provide saliva samples for genotyping and complete extensive on-line medical history, family history, and lifestyle questionnaires. Only results for diseases deemed potentially actionable by an independent advisory board are reported.ResultsWe present our methodology for developing personalized reports containing risks for both genetic and nongenetic factors. Risk estimates are given as relative risk, derived or reported from representative peer-reviewed publications. Estimates of disease prevalence are also provided. Presenting risk as relative risk allows for consistent reporting across multiple diseases and across genetic and nongenetic factors. Using this approach eliminates the need for assumptions regarding population lifetime risk estimates. Publications used for risk reporting are selected based on the strength of the design and study quality.ConclusionCoriell Personalized Medicine Collaborative risk reports demonstrate an approach to communicating risk of complex disease via the web that encompasses risks due to genetic variants along with risks caused by family history and lifestyle factors. Genet Med 2011:13(2):131–139.     

Summarizing recommendations to eliminate weight stigma in prenatal health care settings: A scoping review

ObjectiveAs the prevalence of obesity increases, more women are at risk of potentially experiencing weight stigma in prenatal health care settings. The objective of this scoping review was to summarize the primary literature assessing potential causes of weight stigma in prenatal health care settings and synthesize recommendations for health care providers to improve clinical practice.MethodsA search strategy was developed combining the terms pregnancy, weight stigma, obesity, and prenatal care. A systematic search was completed in the following databases: Medline, EMBASE, PsycInfo, CINAHL, Opengrey, and Proquest.ResultsEighteen resources were included in this review, of which 17 were qualitative, and one was a mixed-methods study design. Weight stigma occurred in prenatal health care settings when providers: avoided weight-related discussions, assumed lifestyle behaviors, and had poor communication when discussing risks associated with obesity. Recommendations to prevent weight stigma included: offering sensitivity training to discuss obesity during pregnancy, implementing a patient-centred approach, including evaluating individual health behaviors, and providing educational resources to patients explaining potential risks and referrals.ConclusionThis review summarizes recommendations to eliminate weight stigma in prenatal health care settings.Practice implicationsThese recommendations can be implemented in clinical practice and can improve the delivery of prenatal care.     

BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors

PurposeBreast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs).MethodsBOADICEA incorporates the effects of truncating variants inBRCA1, BRCA2, PALB2, CHEK2, and ATM; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information.ResultsAmong all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with14.7% of women predicted to have a lifetime risk of ≥17–<30% (moderate risk according to National Institute for Health and Care Excellence [NICE] guidelines) and 1.1% a lifetime risk of ≥30% (high risk).ConclusionThis comprehensive model should enable high levels of BC risk stratification in the general population and women with family history, and facilitate individualized, informed decision-making on prevention therapies and screening.     

How can polygenic inheritance be used in population screening for common diseases?

Advances in genomics have near-term impact on diagnosis and management of monogenic disorders. For common complex diseases, the use of genomic information from multiple loci (polygenic model) is generally not useful for diagnosis and individual prediction. In principle, the polygenic model could be used along with other risk factors in stratified population screening to target interventions. For example, compared to age-based criterion for breast, colorectal, and prostate cancer screening, adding polygenic risk and family history holds promise for more efficient screening with earlier start and/or increased frequency of screening for segments of the population at higher absolute risk than an established screening threshold; and later start and/or decreased frequency of screening for segments of the population at lower risks. This approach, while promising, faces formidable challenges for building its evidence base and for its implementation in practice. Currently, it is unclear whether or not polygenic risk can contribute enough discrimination to make stratified screening worthwhile. Empirical data are lacking on population-based age-specific absolute risks combining genetic and non-genetic factors, on impact of polygenic risk genes on disease natural history, as well as information on comparative balance of benefits and harms of stratified interventions. Implementation challenges include difficulties in integration of this information in the current health-care system in the United States, the setting of appropriate risk thresholds, and ethical, legal, and social issues. In an era of direct-to-consumer availability of personal genomic information, the public health and health-care systems need to prepare for an evidence-based integration of this information into population screening.Genet Med 2013:15(6):437–443     

Diagnosis,treatment and disclosure: A qualitative exploration of participant challenges in a Monogenic Diabetes Registry

PurposeMaturity-onset diabetes of the young (MODY) represents a heterogenous group of monogenic diabetes. Despite its autosomal dominant inheritance, many MODY participants in the University of Chicago Monogenic Diabetes Registry have no family members enrolled. We aimed to gather data on the Registry participants’ experiences in (1) receipt of an accurate diagnosis, (2) decisions regarding disclosure of their MODY genetic test results with biological relatives, and (3) recommendations toward our Registry’s processes and outreach.MethodsWe conducted 20 one-on-one semistructured interviews with adult Registry participants.ResultsAll participants found navigating the health care system challenging because of the providers’ unfamiliarity with MODY and dismissal of its importance post diagnosis. All had shared their results with at least 1 relative, however many found their relatives resistant to engaging with their providers. Participants wanted to receive targeted information on their condition and connect with other participants who have faced similar diagnostic and treatment challenges.ConclusionOur results demonstrate that our probands faced resistance to reclassification of their diabetes from both health care providers and relatives. In an effort to improve cascade testing, the Registry is designing a portal to facilitate participant–research team communication and provide additional supports for participants to involve family members in testing.     

Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

PurposeThe purpose of this document is to provide updated guidance for the genetic evaluation of cardiomyopathy and for an approach to manage secondary findings from cardiomyopathy genes. The genetic bases of the primary cardiomyopathies (dilated, hypertrophic, arrhythmogenic right ventricular, and restrictive) have been established, and each is medically actionable; in most cases established treatments or interventions are available to improve survival, reduce morbidity, and enhance quality of life.MethodsA writing group of cardiologists and genetics professionals updated guidance, first published in 2009 for the Heart Failure Society of America (HFSA), in a collaboration with the American College of Medical Genetics and Genomics (ACMG). Each recommendation was assigned to teams of individuals by expertise, literature was reviewed, and recommendations were decided by consensus of the writing group. Recommendations for family history, phenotype screening of at-risk family members, referral to expert centers as needed, genetic counseling, and cardiovascular therapies, informed in part by phenotype, are presented in the HFSA document.ResultsA genetic evaluation of cardiomyopathy is indicated with a cardiomyopathy diagnosis, which includes genetic testing. Guidance is also provided for clinical approaches to secondary findings from cardiomyopathy genes. This is relevant as cardiomyopathy is the phenotype associated with 27% of the genes on the ACMG list for return of secondary findings. Recommendations herein are considered expert opinion per current ACMG policy as no systematic approach to literature review was conducted.ConclusionGenetic testing is indicated for cardiomyopathy to assist in patient care and management of at-risk family members.     

A review of normative documents on preimplantation genetic testing: Recommendations for PGT-P

PurposeRecently, preimplantation genetic testing (PGT) for polygenic conditions (PGT-P) has been introduced commercially. In view of the lack of specific guidance on this development, we analyzed normative documents on PGT for monogenic conditions (PGT-M) to understand what we can learn from these documents for recommendations for PGT-P.MethodsWe conducted a systematic review of normative guidelines and recommendations on PGT-M. The aim was to understand what the current consensus and disagreements are on ethical acceptability of PGT-M and how this compares with PGT-P.ResultsWe analyzed 38 documents by advisory committees at the national, European, and global level. In total, 2 themes were identified, which included the following: (1) what PGT is considered appropriate for and (2) who can make decisions regarding the use of PGT. Many aspects of PGT-M documents apply to PGT-P as well. Additional factors such as the fact that PGT-P screens for risk indications of multiple polygenic conditions increase ethical difficulties regarding severity, risk, autonomy, and informed decision-making.ConclusionOn the basis of PGT-M normative documents, we conclude that ethical acceptability for PGT-P is limited. Our findings present various factors that have to be considered for the development of guidelines and the appropriateness of PGT.     

A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders

PurposeTo prospectively evaluate the diagnostic and clinical utility of singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic disease.MethodsSingleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center. This occurred in parallel with standard investigations, including single- or multigene panel sequencing when clinically indicated. The diagnosis rate, clinical utility, and impact on management of singleton WES were evaluated.ResultsOf 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group. Clinical management changed following exome diagnosis in 15 of 46 diagnosed participants (32.6%). Twelve relatives received a genetic diagnosis following cascade testing, and 28 couples were identified as being at high risk of recurrence in future pregnancies.ConclusionsThis prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier sequencing test for infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner.Genet Med 18 11, 1090–1096.     

Implementation,adoption, and utility of family health history risk assessment in diverse care settings: evaluating implementation processes and impact with an implementation framework

PurposeThis paper describes the implementation outcomes associated with integrating a family health history–based risk assessment and clinical decision support platform within primary care clinics at four diverse healthcare systems.MethodsA type III hybrid implementation-effectiveness trial. Uptake and implementation processes were evaluated using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework.ResultsOne hundred (58%) primary care providers and 2514 (7.8%) adult patients enrolled. Enrolled patients were 69% female, 22% minority, and 32% Medicare/Medicaid. Compared with their respective clinic’s population, patient-participants were more likely to be female (69 vs. 59%), older (mean age 57 vs. 49), and Caucasian (88 vs. 69%) (all p values <0.001). Female (81.3% of females vs. 78.5% of males, p value = 0.018) and Caucasian (Caucasians 90.4% vs. minority 84.1%, p value = 0.02) patient-participants were more likely to complete the study once enrolled. Patient-participant survey responses indicated MeTree was easy to use (95%), and patient-participants would recommend it to family/friends (91%). Minorities and those with less education reported greatest benefit. Enrolled providers reflected demographics of underlying provider population.ConclusionFamily health history–based risk assessment can be effectively implemented in diverse primary care settings and can effectively engage patients and providers. Future research should focus on finding better ways to engage young adults, males, and minorities in preventive healthcare.     

Patient and provider perspectives on preterm birth risk assessment and communication

ObjectiveTo describe and compare how obstetric patients and care providers view preterm birth risk assessment and communication.MethodsWe conducted eight focus groups with obstetric patients (n = 35) and 16 qualitative interviews with obstetric providers. Grounded theory was used to identify and analyze themes.ResultsPatients' knowledge about preterm birth varied greatly. Similar benefits and risks of preterm birth risk counseling were discussed by patients and providers with notable exceptions: patients cited preparedness as a benefit and providers cited maternal blame, patient alienation, and estimate uncertainty as potential risks. Most patients expressed a desire to know their personalized preterm birth risk during pregnancy. Providers differed in whether they offer universal versus selective, and quantitative versus qualitative, preterm birth risk counseling. Many providers expressed concern about discussing social and structural risk factors for preterm birth.ConclusionWhile many patients desired knowing their personalized preterm birth risk, prenatal care providers’ disclosure practices vary because of uncertainty of estimates, concerns about negative consequences and challenges of addressing systemic inequities and social determinants of health.Practice implicationsGiven the existing asymmetry of information about preterm birth risk, providers should consider patient preferences regarding and potential benefits and risks of such disclosure in their practice.     

Pathways from autism spectrum disorder diagnosis to genetic testing

PurposeThis study examined challenges faced by families and health providers related to genetic testing for autism spectrum disorder (ASD).MethodsThis qualitative study of 14 parents and 15 health providers identified an unstandardized three-step process for families who pursue ASD genetic testing.ResultsStep 1 is the clinical diagnosis of ASD, confirmed by providers practicing alone or in a team. Step 2 is the offer of genetic testing to find an etiology. For those offered testing, step 3 involves the parents’ decision whether to pursue testing. Despite professional guidelines and recommendations, interviews describe considerable variability in approaches to genetic testing for ASD, a lack of consensus among providers, and questions about clinical utility. Many families in our study were unaware of the option for genetic testing; testing decisions by parents appear to be influenced by both provider recommendations and insurance coverage.ConclusionConsideration of genetic testing for ASD should take into account different views about the clinical utility of testing and variability in insurance coverage. Ideally, policy makers from the range of clinical specialties involved in ASD care should revisit policies to clarify the purpose of genetic testing for ASD and promote consensus about its appropriate use.     

Preliminary validation of a consumer-oriented colorectal cancer risk assessment tool compatible with the US Surgeon General’s My Family Health Portrait

PurposeThis study examines the analytic validity of a software tool designed to provide individuals with risk assessments for colorectal cancer based on personal health and family history information. The software is compatible with the US Surgeon General’s My Family Health Portrait (MFHP).MethodsAn algorithm for risk assessment was created using accepted colorectal risk assessment guidelines and programmed into a software tool (MFHP). Risk assessments derived from 150 pedigrees using the MFHP tool were compared with “gold standard” risk assessments developed by three expert cancer genetic counselors.ResultsGenetic counselor risk assessments showed substantial, but not perfect, agreement. MFHP risk assessments for colorectal cancer yielded a sensitivity for colorectal cancer risk of 81% (95% confidence interval: 54–96%) and specificity of 90% (95% confidence interval: 83–94%), as compared with genetic counselor pedigree review. The positive predictive value for risk for MFHP was 48% (95% confidence interval: 29–68%), whereas the negative predictive value was 98% (95% confidence interval: 93–99%). Agreement between MFHP and genetic counselor pedigree review was moderate (κ = 0.54).ConclusionThe analytic validity of the MFHP colorectal cancer risk assessment software is similar to those of other types of screening tools used in primary care. Future investigations should explore the clinical validity and utility of the software in diverse population groups.Genet Med17 9, 753–756.     

Clinical utility of family history for cancer screening and referral in primary care: a report from the Family Healthware Impact Trial

PurposeTo assess the effectiveness of computerized familial risk assessment and tailored messages for identifying individuals for targeted cancer prevention strategies and motivating behavior change.MethodsWe conducted a randomized clinical trial in primary care patients aged 35–65 years using Family Healthware, a self-administered, internet-based tool that collects family history for six common diseases including breast cancer, colon cancer, and ovarian cancer, stratifies risk into three tiers, and provides tailored prevention messages. Cancer screening adherence and consultation were measured at baseline and 6-month follow-up.ResultsOf 3283 participants, 34% were at strong or moderate risk of at least one of the cancers. Family Healthware identified additional participants for whom earlier screening (colon cancer, 4.4%; breast cancer, women ages: 35–39 years, 9%) or genetic assessment (colon cancer, 2.5%; breast cancer, 10%; and ovarian cancer, 4%) may be indicated. Fewer than half were already adherent with risk-based screening. Screening adherence improved for all risk categories with no difference between intervention and control groups. Consultation with specialists did not differ between groups.ConclusionFamily Healthware identified patients for intensified cancer prevention. Engagement of clinicians and patients, integration with clinical decision support, and inclusion of nonfamilial risk factors may be necessary to achieve the full potential of computerized risk assessment.