Predictive Testing Research Articles

The management of BRCA1 and BRCA2 carriers in Singapore.

Singapore is a densely populated small island nation, with a multiethnic and multireligious population. Cancer is the leading cause of death in Singapore. The population is well educated and coupled with greater awareness, there is an increasing demand for genetic testing for hereditary cancer syndromes. In Singapore, the Singapore Cancer Action Network (SCAN) guidelines for referral for genetic testing serves as a guide for clinicians on appropriate referral. We examined the important factors in genetic counselling in such a diverse population, such as acknowledgement of psychosocial impact of BRCA1/2, cultural sensitivity and upskilling of healthcare professionals. Access to genetic services in Singapore is widely available, though the number of patients who undergo testing is lower due to need for out-of-pocket costs and lack of funding from government agencies and insurance companies. The delivery of clinical care and research accrual is performed concurrently in our centre. All patients undergo pre-test counselling before giving informed consent for germline genetic testing and post-test counselling for interpretation of test results. Patients who test positive for BRCA1/2 continue to be on follow up with the cancer genetics clinic for risk-management. Predictive testing is discussed and facilitated for all at-risk relatives. Challenges faced by cancer genetics professionals in Singapore include the high rate of variant of uncertain significance (VUS) and low predictive testing rates. We hold regular support group activities for patients to seek mutual support and to raise overall awareness of BRCA1/2. We believe our comprehensive cancer genetics service serves as a useful model for other Asian countries looking to set up their own unit. We continue to aspire to empower patients, family members and healthcare professionals with cancer genetics knowledge to improve personal and public health.

In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Infants

In vitro dissolution testing conditions that reflect and predict in vivo drug product performance are advantageous, especially for the development of paediatric medicines, as clinical testing in this population is hindered by ethical and technical considerations. The aim of this study was to develop an in vivo predictive dissolution test in order to investigate the impact of medicine co-administration with soft food and drinks on the dissolution performance of a poorly soluble compound. Relevant in vitro dissolution conditions simulating the in vivo gastrointestinal environment of infants were used to establish in vitro-in vivo relationships with corresponding in vivo data. Dissolution studies of montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: infant fasted-state simulated gastric fluid (Pi-FaSSGF; for 1 h) followed by either infant fasted-state or infant fed-state simulated intestinal fluid (FaSSIF-V2 or Pi-FeSSIF, respectively; for 3 h). The dosing scenarios tested reflected in vivo paediatric administration practices: (i.) direct administration of formulation; (ii.) formulation co-administered with vehicles (formula, milk or applesauce). Drug dissolution was significantly affected by co-administration of the formulation with vehicles compared with after direct administration of the formulation. Montelukast dissolution from the granules was significantly higher under fed-state simulated intestinal conditions in comparison with the fasted state and was predictive of the in vivo performance when the granules are co-administered with milk. This study supports the potential utility of the in vitro biorelevant dissolution approach proposed to predict in vivo formulation performance after co-administration with vehicles, in the paediatric population.

Examining information-seeking behavior in genetic testing for cancer predisposition: A qualitative interview study

ObjectiveThis study aims to assess information needs and information sources and seeks to illustrate what at-risk individuals consider motivators of and barriers to information-seeking before and after genetic testing for cancer predisposition. MethodsSemi-structured interviews with people seeking genetic counseling in Switzerland were analyzed qualitatively using thematic analysis. Wilson's model of information behavior was the theoretical framework. ResultsWe identified four themes that illustrate motivators of and barriers to information-seeking: attitudes and emotions; knowledge; social environment; and demographic factors. We also elucidated information needs and collected participants' information sources. ConclusionThis study£s empirical approach helps healthcare professionals to understand their patients' behaviors and wishes concerning information-seeking more concretely than theoretical models alone. The study also identifies information gaps, especially outside the genetic counseling setting. Practice implicationsGenetic counselors and other healthcare professionals need to purposefully assist patients in finding trustworthy and accessible information. Healthcare professionals in all disciplines need to be educated about predictive genetic testing.

An observation regarding Hamilton’s recent criticisms of Kilian’s global real economic activity index

Hamilton (2019) offers several criticisms of the global real economic activity (REA) index suggested in Kilian (2009). This study deals with Hamilton (2019)’s arguments regarding the ability of the index to forecast commodity prices. Using in-sample population-level predictability tests, Hamilton (2019) argues that world industrial production index growth rate performs better than Kilian’s REA Index. We show that from an out-of-sample population-level predictability perspective, the REA index performs just as well if not better than world industrial production index. The Clark and West (2007) no population-level predictability null hypothesis is rejected at the same rate if not higher for the REA index, especially as the forecast horizon increases.

A new test of asset return predictability with an unstable predictor

This study constructs predictive regressions in which the predictable variable exhibits a level shift at some unknown date. We establish novel procedures to test asset return predictability via empirical likelihood (EL) methods based on weighted score equations. Monte Carlo simulations confirm that the EL-based tests perform well in terms of size and power in finite samples.

The world of molecular cytopathology: Predictive testing and precision medicine: Highlights from the eighth International Molecular Cytopathology Meeting in Naples, Italy.

International Perspectives in Cytology was launched in early 2019 with the goal of connecting members of the global cytopathology community as well as providing Cancer Cytopathology readers with a better understanding of the role of cytopathology across the world.1 Although many aspects of cytopathology are similar, the adoption of different technologies and programs in different clinical settings can vary greatly and impact the practice of cytopathology in different countries. For the past several years, the International Molecular Cytopathology Meeting, held annually in Naples, Italy, has focused on providing a global perspective regarding the evolution of molecular pathology in the field of cytopathology with updates on cytological and molecular classifications and novel research.2, 3 In this issue of Cancer Cytopathology, we have presented a series of articles from the eighth meeting, held in December 2019, that focused on the similarities between and the unique practices of lung cancer molecular cytopathology in Europe and the United States, and offered a diverse and international perspective concerning the practice of molecular cytopathology. Over the last 2 decades, the identification of oncogenic drivers in patients with non–small cell lung cancer (NSCLC) has revolutionized diagnostic and therapeutic approaches in molecularly selected subgroups of patients with advanced NSCLC. The drug development and approval process for therapeutic targets has rapidly transformed into an accelerated program with the use of innovative and adaptive study designs and expedited regulatory approval. Recent oncogenic drivers, including RET rearrangements and MET exon 14 skipping mutations, have been included as therapeutic targets for the treatment of patients with advanced NSCLC, in addition to the well-established EGFR and BRAF mutations, ALK and ROS1 rearrangements, and PD-L1 expression, to expand the list of druggable genetic aberrations.4 Predictive molecular testing in pathology and, more specifically, cytopathology, varies from a centralized model in some countries within Europe to a more decentralized model as in the United States. The first article in the series, by Hofman et al, focused on tissue and liquid biopsy testing in patients with NSCLC, taking us through the evolution of molecular pathology test implementation in France from the initial establishment of a national network of molecular genetic centers for cancer to test a limited number of genes by targeted polymerase chain reaction assays, to a second phase with the development of next-generation sequencing technology and all laboratories in France having access to molecular testing, to the more recent implementation of a systematic sequencing approach in which large-panel molecular tests currently are being centralized to a limited number of molecular genetic centers.5 The second article by Siemanowski et al described the practice of routine molecular pathology diagnostics in Germany.6 The authors have highlighted the German model of central comprehensive molecular testing by the Network Genomic Medicine Lung Cancer and the delivery of decentralized patient care at all German comprehensive cancer centers. The article discussed internal quality control, laboratory accreditation, and quality assurance programs and focused specifically on testing for gene fusions in patients with lung cancer.6 The third article by Vigliar et al described predictive molecular testing in Italy, where the universal health care system currently provides a decentralized model, with local laboratories performing in-house molecular testing based on guidelines from the Italian Society of Anatomic Pathology and Diagnostic Cytopathology and the Italian Division of the International Academy of Pathology.7 The final review article by VanderLaan and Roy-Chowdhuri explored the current state of NSCLC molecular testing in the United States, and focused on biomarkers that currently are used in the therapeutic approach for these patients and the promise of novel, unconventional, cytologic “liquid biopsy” substrates that potentially can be incorporated into testing paradigms.8 The final strokes to this special series were added by a commentary from Rossi et al.9 The authors concluded with a philosophical discussion of the “ideal” specimen and discussed how cytology and surgical specimens coexist in an alternative and parallel world, with expanding possibilities and opportunities for molecular pathology. No specific funding was disclosed. The authors made no disclosures.

Molecular predictive testing in precision oncology: The Italian experience.

In this review, we describe molecular pathology testing to predict response to targeted treatment of solid tumors, focusing on Italian routine clinical practice. The combination of the universal health care system organized at national, regional, and local levels has led a decentralized model, with a large number of local laboratories performing in-house molecular testing following guidelines issued and external quality assessment organized by the Italian Society of Pathology and Cytopathology-Italian Division of the International Academy of Pathology. In this framework, in the early days of predictive testing, sponsored informatics platforms support to set up national programs that aimed to integrate the activity of oncologists and pathologists to test cancer patients for druggable alterations. More recently, reimbursement for molecular testing is being covered completely by the Italian National Health Service. In the near future, considering the development of complex technologies, we expect that outsourcing samples to next-generation sequencing referral laboratories will take place.

Predictive molecular pathology of lung cancer in Germany with focus on gene fusion testing: Methods and quality assurance.

Predictive molecular testing has become an important part of the diagnosis of any patient with lung cancer. Using reliable methods to ensure timely and accurate results is inevitable for guiding treatment decisions. In the past few years, parallel sequencing has been established for mutation testing, and its use is currently broadened for the detection of other genetic alterations, such as gene fusion and copy number variations. In addition, conventional methods such as immunohistochemistry and in situ hybridization are still being used, either for formalin-fixed, paraffin-embedded tissue or for cytological specimens. For the development and broad implementation of such complex technologies, interdisciplinary and regional networks are needed. The Network Genomic Medicine (NGM) has served as a model of centralized testing and decentralized treatment of patients and incorporates all German comprehensive cancer centers. Internal quality control, laboratory accreditation, and participation in external quality assessment is mandatory for the delivery of reliable results. Here, we provide a summary of current technologies used to identify patients who have lung cancer with gene fusions, briefly describe the structures of NGM and the national NGM (nNGM), and provide recommendations for quality assurance.

Personalized drug testing in a patient with non-small-cell lung cancer using cultured cancer cells from pleural effusion.

ObjectivePatients with non-small-cell lung cancer (NSCLC) and primary or acquired resistance do not respond to targeted drugs. We explored whether cancer cells can be cultured from liquid biopsies from patients with primary resistance to tyrosine kinase inhibitors (TKIs). We aimed to predict patients’ responses to drugs according to in vitro drug testing results.MethodsCancer cell cultures were established from the pleural effusion of a patient with TKI-resistant NSCLC using a conditional reprogramming technique. Phenotypic drug sensitivity tests were performed using the Cell Counting Kit-8 assay. We tested individual drugs and compared the synergistic and inhibitory effects of drug combinations.ResultsThe results of our in vitro sensitivity test using the combination of cisplatin and pemetrexed were correlated with the patient’s response.ConclusionThis represents the first successful report of predictive testing for combination therapy in patients with epidermal growth factor receptor-mutant NSCLC and primary TKI resistance. This strategy should be applicable to both chemotherapies and targeted therapies, and it will significantly improve the clinical treatment and management of patients with NSCLC and primary or acquired resistance to targeted therapies, as well as patients lacking targetable mutations.

Opinions of African American adults about the use of apolipoprotein L1 (ApoL1) genetic testing in living kidney donation and transplantation.

Apolipoprotein L1 (ApoL1) predictive genetic testing for kidney disease, and its emerging role in transplantation, remains controversial as it may exacerbate underlying disparities among African Americans (AAs) at increased risk. We conducted an online simulation among AAs (N=585) about interest in ApoL1 testing and its cofactors, under 2 scenarios: as a potential living donor (PLD), and as a patient awaiting transplantation. Most respondents (61%) expressed high interest in genetic testing as a PLD: age ≥35years (adjusted odds ratio [aOR], 1.75; 95% confidence interval [CI], 1.18, 2.60, P=.01), AA identity (aOR, 1.67; 95% CI, 1.02, 2.72, P=.04), perceived kidney disease risk following donation (aOR, 1.68; 95% CI, 1.03, 2.73, P=.03), interest in genetics (aOR, 2.89; 95% CI, 1.95, 4.29, P=.001), and genetics self-efficacy (aOR, 2.38; 95% CI, 1.54, 3.67, P=.001) were positively associated with ApoL1 test interest. If awaiting transplantation, most (89%) believed that ApoL1 testing should be done on AA deceased donors, and older age (aOR, 1.85; 95% CI, 1.03, 3.32, P=.04) and greater interest in genetics (aOR, 2.61; 95% CI, 1.41, 4.81, P=.002) were associated with interest in testing deceased donors. Findings highlight strong support for ApoL1 testing in AAs and the need to examine such opinions among PLDs and transplant patients to enhance patient education efforts.

Segregation analysis of the BRCA2 c.9227G>T variant in multiple families suggests a pathogenic role in breast and ovarian cancer predisposition

Classification of variants in the BRCA1 and BRCA2 genes has a major impact on the clinical management of subjects at high risk for breast and ovarian cancer. The identification of a pathogenic variant allows for early detection/prevention strategies in healthy carriers as well as targeted treatments in patients affected by BRCA-associated tumors. The BRCA2 c.9227G>T p.(Gly3076Val) variant recurs in families from Northeast Italy and is rarely reported in international databases. This variant substitutes the evolutionary invariant glycine 3076 with a valine in the DNA binding domain of the BRCA2 protein, thus suggesting a high probability of pathogenicity. We analysed clinical and genealogic data of carriers from 15 breast/ovarian cancer families in whom no other pathogenic variants were detected. The variant was shown to co-segregate with breast and ovarian cancer in the most informative families. Combined segregation data led to a likelihood ratio of 81,527:1 of pathogenicity vs. neutrality. We conclude that c.9227G>T is a BRCA2 pathogenic variant that recurs in Northeast Italy. It can now be safely used for the predictive testing of healthy family members to guide preventive surgery and/or early tumor detection strategies, as well as for PARP inhibitors treatments in patients with BRCA2-associated tumors.

Long-Term Follow-Up Study on the Uptake of Genetic Counseling and Predictive DNA Testing in Inherited Cardiac Conditions.

Inherited cardiac conditions present with a wide range of symptoms and may even result in sudden cardiac death. Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In 2 previous cohort studies of 115 probands with a pathogenic variant, family uptake of genetic counseling was assessed in the first year(s) after test result disclosure to the proband. This study assesses uptake in these cohorts in the 14 to 23 years following disclosure. Uptake was determined retrospectively using patient records. First-degree relatives, and second-degree relatives of a deceased first-degree relative suspected of having an inherited cardiac condition, were considered eligible. Of 717 eligible relatives (598 first-degree and 119 second-degree relatives), 60% attended genetic counseling. Most of them (68.6%) attended genetic counseling in the first year. A total of 98.4% of counseled relatives pursued predictive DNA testing. A total of 49.2% was identified as carrier. Median time between disclosure to the proband and counseling of relatives was 6 months (range: 0-187 months). Attending genetic counseling was observed more frequently in first-degree relatives, female relatives, primary arrhythmia syndromes, relatives with manifest inherited cardiac condition, relatives without children and families with sudden cardiac death in first-degree relatives <40 years. During median follow-up of 16 years, 60.0% of relatives attended genetic counseling, with 41.0% in the first year. Our results may suggest that some relatives are not or inadequately informed or that barriers against genetic counseling are present. Further research is needed into interventions facilitating family communication, increasing awareness among families and healthcare professionals, and lowering thresholds for genetic counseling.

Abstract 4159: Ovarian cancer ex vivo 3D tumor cultures predict patient specific drug sensitivity

Abstract Introduction While systemic treatment has been quite static in the past decade in ovarian cancer, the challenge for the coming years is to stratify patients for optimal and new treatment strategies, such as targeting DNA damage response pathways, or immune modulation. Patient primary tumor from resections, biopsy or ascites can be cultured such that tumor heterogeneity and resident immune cells are preserved. These can be used to predict treatment response in patients or to test new cancer therapies. Here we present a high throughput short-term 3D ex-vivo culture platform combined with high content image-based analysis. This platform allows visualization and quantification of standard of care therapy and new drugs on fresh and cryopreserved patient derived ovarian cancer tumoroids. Methods Patients with advanced primary or relapsing ovarian carcinoma are included in ongoing multi-center clinical trials in the Netherlands. Ovarian cancer derived tumoroids, freshly isolated or cryopreserved, are embedded in a protein-rich hydrogel and exposed to up to 20 drugs during a short term 3D culture. The automated high content imaging analysis platform measures a large panel of tumoroid morphological features, and responses such as tumor cell killing, growth arrest and local invasion are measured to define the response for each drug. In addition, clinical response data from the ongoing trials are collected to be correlated to clinical outcome of patients treated with systemic therapy. Results We present results of drug sensitivity testing in patient-derived primary tumor cells of fresh and cryopreserved ascites and solid tumor. Patient-specific drug sensitivity is identified for up to 20 drugs including standard of care (e.g. carboplatin, paclitaxel) and novel treatment strategies (e.g. PARP inhibitors). Activity of immunomodulatory drugs were also monitored successfully in vitro. Accurate response evaluation demonstrates the feasibility of high-throughput drug screening on patient primary material within OcellO's platform. Our results show a high reproducibility in testing freshly isolated or cryopreserved material, highlighting the potential of a cryopreserved collection of patient derived primary material to test new drugs. Conclusion OcellO's advanced 3D image analysis of patient primary material represents a rapid and biologically relevant approach to test various candidate compounds (e.g. antibodies, antibody-drug conjugates and small molecules) for ovarian cancer. The availability of drug response data combined with patient clinical data, including BRCA mutation and cytology/histology pathologist evaluation is expected to support drug discovery, improve the efficiency of clinical trials and establish predictive testing in the clinical setting. Citation Format: Fanny Grillet, Abbas Jariani, Juul Overkamp, Lidia Daszkiewicz, Kuan Yan, Leo S. Price, Willemijn Vader. Ovarian cancer ex vivo 3D tumor cultures predict patient specific drug sensitivity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4159.

Rare tumors as leading symptom of hereditary tumor syndromes

Monogenic hereditary tumor syndromes or tumor disposition syndromes (TDS) are based on germline/constitutional mutations in key genes of carcinogenesis. Early onset and aclustering of tumors belonging to atypical spectrum in the personal or family history are indicators for ahereditary form. In particular, rare specific tumors occur relatively frequently in the context of TDS. Based on aliterature search the current article presents information on which TDS should be considered for differential diagnosis (DD) in the presence of arare tumor. The identification of acausal germline mutation in the index patient is important for the DD, the evaluation of recurrence risks, and predictive testing of asymptomatic at-risk family members. In TDS with autosomal dominant inheritance, it is often possible to identify several high-risk individuals in the affected families. Early detection and correct classification are of high clinical relevance as the patients and persons at risk can often be offered effective preventive procedures (surveillance, prophylactic operations), and in some cases, special therapeutic options exist. TDS are paradigmatic for an extremely successful concept of preventive oncology and personalized medicine. The introduction of new methods of high-throughput sequencing (next generation sequencing) enables amore effective genetic diagnosis, but also poses achallenge for the interpretation of findings and counseling. Referral to multidisciplinary expert centers is useful for care of the families.

New testing approaches for mean–variance predictability

We propose parametric tests for serial correlation in levels and squares that exploit the non-normality of financial returns. Our tests are robust to distributional misspecification. Furthermore, our mean predictability tests can be robustified against time-varying volatility. Local power analyses confirm their gains over existing methods, while Monte Carlo exercises assess their finite sample reliability. We apply our tests to quarterly returns on the five Fama–French factors for international stocks, whose distributions are mostly symmetric but fat-tailed. Our results highlight noticeable differences across regions and factors and confirm the numerical sensitivity of the usual tests to influential observations.

A comprehensive DNA panel next generation sequencing approach supporting diagnostics and therapy prediction in neurooncology

Recent updates in the classification of central nervous system (CNS) tumors have increased the need for molecular testing. Assessment of multiple alterations in parallel, complex combinations of gene sequence and chromosomal changes, as well as therapy prediction by identification of actionable mutations are the major challenges. We here report on a customized next generation sequencing (NGS)-based DNA panel assay that combines diagnostic and predictive testing and -as a comprehensive approach- allows for simultaneous single nucleotide variant (SNP) / small insertion/deletion (InDel), copy number variation (CNV) and loss of heterozygosity (LOH) detection. We analyzed formalin-fixed and paraffin-embedded (FFPE) DNA from a total of 104 patients with CNS tumors. After amplicon capture-based library preparation, sequencing was performed on the relatively cost-efficient Illiumina MiniSeq platform and evaluated with freely available bioinformatical tools. 57 genes for exonic SNP/InDel calling (19 of those in intronic regions for CNV analysis), 3 chromosomal arms and 4 entire chromosomes for CNV and LOH analysis were covered. Results were extensively validated. Our approach yielded high accuracy, sensitivity and specificity. It led to refined diagnoses in a relevant number of analyzed cases, reliably enabled complex subclassifications (e.g. for medulloblastomas) and identified actionable targets for clinical use. Thus, our single-platform approach is an efficient and powerful tool to comprehensively support molecular testing in neurooncology. Future functionality is guaranteed as novel upcoming biomarkers can be easily incorporated in a modular panel design.

Restricted Likelihood Ratio Tests in Predictive Regression

Chen and Deo (2009a) proposed procedures based on restricted maximum likelihood (REML) for estimation and inference in the context of predictive regression. Their method achieves bias reduction in both estimation and inference which assists in overcoming size distortion in predictive hypothesis testing. This paper provides extensions of the REML approach to more general cases which allow for drift in the predictive regressor and multiple regressors. It is shown that without modification the REML approach is seriously oversized and can have unit rejection probability in the limit under the null when the drift in the regressor is dominant. A limit theory for the modified REML test is given under a localized drift specification that accommodates predictors with varying degrees of persistence. The extension is useful in empirical work where predictors typically involve stochastic trends with drift and where there are multiple regressors. Simulations show that with these modifications, the good performance of the restricted likelihood ratio test (RLRT) is preserved and that RLRT outperforms other predictive tests in terms of size and power even when there is no drift in the regressor.

Genetics of Chronic Traumatic Encephalopathy.

Although chronic traumatic encephalopathy (CTE) garners substantial attention in the media and there have been marked scientific advances in the last few years, much remains unclear about the role of genetic risk in CTE. Two athletes with comparable contact-sport exposure may have varying amounts of CTE neuropathology, suggesting that other factors, including genetics, may contribute to CTE risk and severity. In this review, we explore reasons why genetics may be important for CTE, concepts in genetic study design for CTE (including choosing controls, endophenotypes, gene by environment interaction, and epigenetics), implicated genes in CTE (including APOE, MAPT, and TMEM106B), and whether predictive genetic testing for CTE should be considered.

Guided screen for synergistic three-drug combinations.

Combinations of three or more drugs are routinely used in various medical fields such as clinical oncology and infectious diseases to prevent resistance or to achieve synergistic therapeutic benefits. The very large number of possible high-order drug combinations presents a formidable challenge for discovering synergistic drug combinations. Here, we establish a guided screen to discover synergistic three-drug combinations. Using traditional checkerboard and recently developed diagonal methods, we experimentally measured all pairwise interactions among eight compounds in Erwinia amylovora, the causative agent of fire blight. Showing that synergy measurements of these two methods agree, we predicted synergy/antagonism scores for all possible three-drug combinations by averaging the synergy scores of pairwise interactions. We validated these predictions by experimentally measuring 35 three-drug interactions. Therefore, our guided screen for discovering three-drug synergies is (i) experimental screen of all pairwise interactions using diagonal method, (ii) averaging pairwise scores among components to predict three-drug interaction scores, (iii) experimental testing of top predictions. In our study, this strategy resulted in a five-fold reduction in screen size to find the most synergistic three-drug combinations.

The emerging field of polygenic risk scores and perspective for use in clinical care.

Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes and cancer. Genome-wide association studies (GWAS) have been invaluable in identifying single-nucleotide polymorphisms (SNPs) associated with increased or decreased risk for hundreds of complex disorders. For a given disease, SNPs can be combined to generate a cumulative estimation of risk known as a polygenic risk score (PRS). After years of research, PRSs are increasingly used in clinical settings. In this article, we will review the literature on how both genome-wide and restricted PRSs are developed and the relative merit of each. The validation and evaluation of PRSs will also be discussed, including the recognition that PRS validity is intrinsically linked to the methodological and analytical approach of the foundation GWAS together with the ethnic characteristics of that cohort. Specifically, population differences may affect imputation accuracy, risk magnitude and direction. Even as PRSs are being introduced into clinical practice, there is a push to combine them with clinical and demographic risk factors to develop a holistic disease risk. The existing evidence regarding the clinical utility of PRSs is considered across four different domains: informing population screening programs, guiding therapeutic interventions, refining risk for families at high risk, and facilitating diagnosis and predicting prognostic outcomes. The evidence for clinical utility in relation to five well-studied disorders is summarized. The potential ethical, legal and social implications are also highlighted.