A systematic framework for selecting gene-condition pairs for inclusion in newborn sequencing panels: Early Check implementation.

PURPOSE: Research is underway worldwide to investigate the feasibility, acceptability, and utility of sequencing-based newborn screening. Different methods have been used to select gene-condition pairs for screening, leading to highly inconsistent gene lists across studies. METHODS: Early Check developed and utilized actionability-based frameworks for evaluating gene-condition pairs for inclusion in newborn panels (Panel 1 - high actionability, Panel 2 - possible actionability). A previously developed framework, the Age-based Semi Quantitative Metric (ASQM), was adapted. Increasing ASQM scores, with a maximum of 15, suggest greater actionability. Wilcoxon tests were performed to compare Panel 1 gene-condition pairs on the Recommended Uniform Screening Panel (RUSP) to non-RUSP pairs. RESULTS: In our first round of assessment, Early Check identified 178 gene-condition pairs for inclusion in Panel 1 and 29 for Panel 2. Median ASQM scores of RUSP conditions on Panel 1 was 12 (range 4 to 15) and non-RUSP was 13 (range 9 to 15). Median scores for Panel 2 was 10 (range 6 to 14). CONCLUSION: The Early Check frameworks provide a transparent, semiquantitative, and reproducible methodology for selecting gene-condition pairs for NBS sequencing pilot studies that may inform future integration of genomic sequencing into population-level NBS. Collaborative efforts among newborn sequencing studies to establish shared criteria is needed to enhance cross-study comparisons.

Should Scotland provide genome-wide sequencing for the diagnosis of rare developmental disorders? A cost-effectiveness analysis.

AIMS: This study aims to evaluate the cost effectiveness of genetic and genomic testing strategies for the diagnosis of rare developmental disorders in NHS Scotland. METHODS: Six genetic and genomic testing strategies were evaluated using a decision tree model. First-line, second-line and last-resort trio genome sequencing (GS), and second-line and last-resort trio exome sequencing (ES) were compared with standard genetic testing. The cost effectiveness of each strategy was expressed in terms of incremental cost per additional diagnosis. The impact of uncertainty on cost-effectiveness results was explored using deterministic and probabilistic sensitivity analysis. RESULTS: 2nd-line ES was a cost-saving option, increasing diagnostic yield by 13.9% and decreasing cost by £1027 per trio compared to standard genetic testing. Compared to ES, strategies involving GS increased costs significantly, with only a moderate or zero improvement in diagnostic yield. Sensitivity analysis indicated that significant reductions in cost or improvements in diagnostic yield are required before 1st-line GS becomes cost effective. CONCLUSION: 2nd-line ES (after chromosomal microarray; replacing gene panel testing) for the diagnosis of developmental disorders is a cost-saving option for the Scottish NHS. Ongoing economic evaluation is required to monitor the evolving cost and diagnostic yield of GS and ES over time.

Implementation of a dyadic nomenclature for monogenic diseases.

A core task when establishing the strength of evidence for a gene's role in a monogenic disorder is determining the appropriate disease entity to curate. Establishing this concept determines which evidence can be applied and quantified toward the final gene-disease validity, variant pathogenicity, or actionability classification. Genes with implications in more than one phenotype can necessitate a process of lumping and splitting, disease reorganization, and updates to disease nomenclature. Reappraisal of the names that are used as labels for disease entities is therefore a necessary and perpetual process. The Clinical Genome Resource (ClinGen), in collaboration with representatives from Monarch Disease Ontology (Mondo) and Online Inheritance in Man (OMIM), formed the Disease Naming Advisory Committee (DNAC) to develop guidance for groups faced with the need to establish the "curated disease entity" for gene-phenotype validity and variant pathogenicity and to update disease names for clinical use when necessary. The objective of this group was to harmonize guidance for disease naming across these nosologic entities and among ClinGen curation groups in collaboration with other disease-related professional groups. Here, we present the initial guidance developed by the DNAC with representative examples provided by the ClinGen expert panels and working groups that warranted nomenclature updates. We also discuss the broader implications of these efforts and their benefits for harmonization of gene-disease validity curation. Overall, this work sheds light on current inconsistencies and/or discrepancies and is designed to engage the broader community on how ClinGen defines monogenic disorders using a consistent approach for disease naming.

Group-based medical mistrust in genomic medicine: Associations with patient and provider perceptions of a specialty clinical encounter.

OBJECTIVE: Investigating associations between group-based medical mistrust (GBMM) and perceptions of patient-provider encounters can identify one mechanism through which GBMM may influence health outcomes and serve as a barrier to equitable healthcare. The present study investigated associations between GBMM reported by caregivers of children with a possibly genetic condition and caregivers' and providers' perceptions of a specialty care appointment discussing diagnostic plans. METHODS: Caregivers (N=177) completed the GBMM scale and other measures prior to their child's initial specialty clinic visit. After the visit, they reported their perceptions of the visit, including patient-centeredness and satisfaction with care. Providers (N=6) reported their perceptions of patient engagement. RESULTS: Multivariable linear regression showed that higher caregiver GBMM was associated with caregivers' lower satisfaction with care (p<0.01) and more negative perceptions of every domain of patient-centeredness (p=0.001-0.04). Multilevel modeling showed that higher caregiver GBMM was associated with more negative provider perceptions of caregivers' preparedness to participate in care (p=0.03), likely treatment compliance (p=0.03), and relevance of questions asked during visit (p=0.04). CONCLUSION: Our findings extend evidence for detrimental effects of GBMM on patient satisfaction to caregivers of pediatric patients and offer new evidence for associations with healthcare providers' perceptions of caregivers' engagement with care.

Advancing Genetic Testing in Kidney Diseases: Report From a National Kidney Foundation Working Group.

About 37 million people in the United States have chronic kidney disease, a disease that encompasses multiple causes. About 10% or more of kidney diseases in adults and as many as 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the benefits and logistics of genetic testing is needed to advance the implementation of genetic testing in chronic kidney diseases. Accordingly, the National Kidney Foundation convened a Working Group of experts with diverse expertise in genetics, nephrology, and allied fields to develop recommendations for genetic testing for monogenic disorders and to identify genetic risk factors for oligogenic and polygenic causes of kidney diseases. Algorithms for clinical decision making on genetic testing and a road map for advancing genetic testing in kidney diseases were generated. An important aspect of this initiative was the use of a modified Delphi process to reach group consensus on the recommendations. The recommendations and resources described herein provide support to nephrologists and allied health professionals to advance the use of genetic testing for diagnosis and screening of kidney diseases.

Noninvasive Pressure-Volume Loops Predict Major Adverse Cardiac Events in Heart Failure With Reduced Ejection Fraction.

Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by ventricular remodeling and impaired myocardial energetics. Left ventricular pressure-volume (PV) loop analysis can be performed noninvasively using cardiovascular magnetic resonance (CMR) imaging to assess cardiac thermodynamic efficiency. Objectives: The aim of the study was to investigate whether noninvasive PV loop parameters, derived from CMR, could predict major adverse cardiac events (MACE) in HFrEF patients. Methods: PV loop parameters (stroke work, ventricular efficiency, external power, contractility, and energy per ejected volume) were computed from CMR cine images and brachial blood pressure. The primary end point was MACE (cardiovascular death, heart failure (HF) hospitalization, myocardial infarction, revascularization, ventricular tachycardia/fibrillation, heart transplantation, or left ventricular assist device implantation within 5 years). Associations between PV loop parameters and MACE were evaluated using multivariable Cox regression. Results: One hundred and sixty-four HFrEF patients (left ventricular ejection fraction ≤40%, age 63 [IQR: 55-70] years, 79% male) who underwent clinical CMR examination between 2004 and 2014 were included. Eighty-eight patients (54%) experienced at least one MACE after an average of 2.8 years. Unadjusted models demonstrated a significant association between MACE and all PV loop parameters (P < 0.05 for all), HF etiology (P < 0.001), left ventricular ejection fraction (P = 0.003), global longitudinal strain (P < 0.001), and N-terminal prohormone of brain natriuretic peptide level (P = 0.001). In the multivariable Cox regression analysis adjusted for age, sex, hypertension, diabetes, and HF etiology, ventricular efficiency was associated with MACE (HR: 1.04 (95% CI: 1.01-1.08) per-% decrease, P = 0.01). Conclusions: Ventricular efficiency, derived from noninvasive PV loop analysis from standard CMR scans, is associated with MACE in patients with HFrEF.

Normative values for body composition in 22,191 healthy Norwegian adults 20-99 years: The HUNT4 study.

BACKGROUND: Body mass, body mass index (BMI), and body composition components are essential for health and longevity. Considering the influence of demographic factors on body composition, there is a need for tailored reference values based on age-, sex-, and geography. We aimed to construct a comprehensive reference material on body composition in healthy Norwegian adults. METHODS: In this cross-sectional study, we estimated age- and sex-specific reference values for body-, fat-, and muscle mass variables using multi-frequency bioelectrial impedance analysis (such as body fat percentage, skeletal muscle mass and visceral fat area) in 22,191 healthy adults aged 20-99 years participating in the Trøndelag Health Study 4 (HUNT4). We calculated the fat mass and skeletal muscle mass index as the total fat and muscle mass relative to height squared and used general linear models to explore the associations between physical activity (PA), BMI, and age. RESULTS: With a BMI (kg/m2) of 25.4 (SD 5.1) and 26.0 (4.5) for women and men, respectively, the youngest age group (20-39 yrs) had a lower BMI compared to their counterparts aged 40-59 years (26.3 [4.5] and 27.5 [3.8]) and ≥ 60 years (25.7 [4.1] and 26.5 [3.4]), respectively. Those aged 20-39 years also had the lowest values for the different body fat variables measured. Fat mass index (kg/m2) was 8.41 (4.00) and 5.81 (3.29) for women and men aged 20-39 years, respectively, compared to 9.25 (3.21) and 6.86 (2.46) for those aged ≥60 years. The oldest age group had the lowest values for the various muscle mass variables; women and men aged 60+ years had a skeletal muscle mass index (kg/m2) of 8.91 (0.85) and 10.96 (1.00), respectively. Corresponding values for those aged 20-39 years were 9.33 (0.97) and 11.49 (1.15). For all age groups and both sexes, regular physical activity was associated with lower levels of fat mass, whereas the association between muscle mass and PAwas less conclusive. When using body fat percentage as an obesity measure, we observed a much higher obesity prevalence (41.2%) in the study population compared to BMI (17.3%). CONCLUSIONS: Our study offers a comprehensive reference for body composition among healthy adults in Norway, aiding the identification of abnormal fat and muscle mass values across age groups. We also highlight that BMI often misclassifies individuals with adiposity levels in the overweight or obese category as lean. Therefore, incorporating body composition when defining obesity could enable early intervention to prevent cardiometabolic diseases.

Generating Clinical-Grade Gene-Disease Validity Classifications Through the ClinGen Data Platforms.

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation. Here we review the work of ClinGen in developing a curation infrastructure that supports the standardization, harmonization, and dissemination of Gene-Disease Validity data through the creation of frameworks and the utilization of common data standards. This infrastructure is based on several applications, including the ClinGen GeneTracker, Gene Curation Interface, Data Exchange, GeneGraph, and website.

Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort.

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.

Correction: Foss et al. The Rise of Population Genomic Screening: Characteristics of Current Programs and the Need for Evidence Regarding Optimal Implementation. J. Pers. Med. 2022, 12, 692.

There was an error in the original publication [...].

Post-death Vesicles of Senescent Bone Marrow Mesenchymal Stromal Polyploids Promote Macrophage Aging and Breast Cancer.

Potential systemic factors contributing to aging-associated breast cancer (BC) remain elusive. Here, we reveal that the polyploid giant cells (PGCs) that contain more than two sets of genomes prevailing in aging and cancerous tissues constitute 5-10% of healthy female bone marrow mesenchymal stromal cells (fBMSCs). The PGCs can repair DNA damage and stimulate neighboring cells for clonal expansion. However, dying PGCs in advanced-senescent fBMSCs can form "spikings" which are then separated into membraned mtDNA-containing vesicles (Senescent PGC-Spiking Bodies; SPSBs). SPSB-phagocytosed macrophages accelerate aging with diminished clearance on BC cells and protumor M2 polarization. SPSB-carried mitochondrial OXPHOS components are enriched in BC of elder patients and associated with poor prognosis. SPSB-incorporated breast epithelial cells develop aggressive characteristics and PGCs resembling the polyploid giant cancer cells (PGCCs) in clonogenic BC cells and cancer tissues. These findings highlight an aging BMSC-induced BC risk mediated by SPSB-induced macrophage dysfunction and epithelial cell precancerous transition. SIGNIFICANCE: Mechanisms underlying aging-associated cancer risk remain unelucidated. This work demonstrates that polyploid giant cells (PGCs) in bone marrow mesenchymal stromal cells (BMSCs) from healthy female bone marrow donors can boost neighboring cell proliferation for clonal expansion. However, the dying-senescent PGCs in the advanced-senescent fBMSCs can form "spikings" which are separated into mitochondrial DNA (mtDNA)-containing spiking bodies (senescent PGC-spiking bodies; SPSBs). The SPSBs promote macrophage aging and breast epithelial cell protumorigenic transition and form polyploid giant cancer cells. These results demonstrate a new form of ghost message from dying-senescent BMSCs, that may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk.

Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms.

PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both Sequence Ontology (SO) and Human Phenotype Ontology (HPO) ontologies. Gene Curation Coalition member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Melanin: a unifying theory of disease as exemplified by Parkinson's, Alzheimer's, and Lewy body dementia.

Melanin, a ubiquitous dark pigment, plays important roles in the immune system, including scavenging reactive oxygen species formed in response to ultraviolet radiation absorption, absorbing metals, thermal regulation, drug uptake, innate immune system functions, redox, and energy transduction. Many tissue types, including brain, heart, arteries, ovaries, and others, contain melanin. Almost all cells contain precursors to melanin. A growing number of diseases in which there is a loss of melanin and/or neuromelanin are increasingly thought to have infectious etiologies, for example, Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body Dementia (LBD), and vitiligo. AD, PD, LBD, and vitiligo have been linked with herpesvirus, which enters melanosomes and causes apoptosis, and with gut dysbiosis and inflammation. Herpesvirus is also linked with gut dysbiosis and inflammation. We theorize that under normal healthy states, melanin retains some of the energy it absorbs from electromagnetic radiation, which is then used to fuel cells, and energy from ATP is used to compliment that energy supply. We further theorize that loss of melanin reduces the energy supply of cells, which in the case of AD, PD, and LBD results in an inability to sustain immune system defenses and remove the plaques associated with the disease, which appear to be part of the immune system's attempt to eradicate the pathogens seen in these neurodegenerative diseases. In addition, in an attempt to explain why removing these plaques does not result in improvements in cognition and mood and why cognitions and moods in these individuals have ebbs and flows, we postulate that it is not the plaques that cause the cognitive symptoms but, rather, inflammation in the brain resulting from the immune system's response to pathogens. Our theory that energy retained in melanin fuels cells in an inverse relationship with ATP is supported by studies showing alterations in ATP production in relationship to melanin levels in melanomas, vitiligo, and healthy cells. Therefore, alteration of melanin levels may be at the core of many diseases. We propose regulating melanin levels may offer new avenues for treatment development.

Parent-Reported Clinical Utility of Pediatric Genomic Sequencing.

BACKGROUND AND OBJECTIVES: Genomic sequencing (GS) is increasingly used for diagnostic evaluation, yet follow-up care is not well understood. We assessed clinicians' recommendations after GS, parent-reported follow-up, and actions parents initiated in response to learning their child's GS results. METHODS: We surveyed parents of children who received GS through the Clinical Sequencing Evidence Generating Research consortium ∼5 to 7 months after return of results. We compared the proportion of parents who reported discussing their child's result with a clinician, clinicians' recommendations, and parents' follow-up actions by GS result type using χ2 tests. RESULTS: A total of 1188 respondents completed survey measures on recommended medical actions (n = 1187) and/or parent-initiated actions (n = 913). Most parents who completed recommended medical actions questions (n = 833, 70.3%) reported having discussed their child's GS results with clinicians. Clinicians made recommendations to change current care for patients with positive GS results (n = 79, 39.1%) more frequently than for those with inconclusive (n = 31, 12.4%) or negative results (n = 44, 11.9%; P < .001). Many parents discussed (n = 152 completed, n = 135 planned) implications of GS results for future pregnancies with a clinician. Aside from clinical recommendations, 13.0% (n = 119) of parents initiated changes to their child's health or lifestyle. CONCLUSIONS: In diverse pediatric clinical contexts, GS results can lead to recommendations for follow-up care, but they likely do not prompt large increases in the quantity of care received.

Age-Based Genomic Screening during Childhood: Ethical and Practical Considerations in Public Health Genomics Implementation.

Genomic sequencing offers an unprecedented opportunity to detect inherited variants that are implicated in rare Mendelian disorders, yet there are many challenges to overcome before this technology can routinely be applied in the healthy population. The age-based genomic screening (ABGS) approach is a novel alternative to genome-scale sequencing at birth that aims to provide highly actionable genetic information to parents over the course of their child's routine health care. ABGS utilizes an established metric to identify conditions with high clinical actionability and incorporates information about the age of onset and age of intervention to determine the optimal time to screen for any given condition. Ongoing partnerships with parents and providers are instrumental to the co-creation of educational resources and strategies to address potential implementation barriers. Implementation science frameworks and informative empirical data are used to evaluate strategies to establish this unique clinical application of targeted genomic sequencing. Ultimately, a pilot project conducted in primary care pediatrics clinics will assess patient and implementation outcomes, parent and provider perspectives, and the feasibility of ABGS. A validated, stakeholder-informed, and practical ABGS program will include hundreds of conditions that are actionable during infancy and childhood, setting the stage for a longitudinal implementation that can assess clinical and health economic outcomes.

Information-seeking preferences in diverse patients receiving a genetic testing result in the Clinical Sequencing Evidence-Generating Research (CSER) study.

PURPOSE: Accurate and understandable information after genetic testing is critical for patients, family members, and professionals alike. METHODS: As part of a cross-site study from the Clinical Sequencing Evidence-Generating Research consortium, we investigated the information-seeking practices among patients and family members at 5 to 7 months after genetic testing results disclosure, assessing the perceived utility of a variety of information sources, such as family and friends, health care providers, support groups, and the internet. RESULTS: We found that individuals placed a high value on information obtained from genetics professionals and health care workers, independent of genetic testing result case classifications as positive, inconclusive, or negative. The internet was also highly utilized and ranked. Study participants rated some information sources as more useful for positive results compared with inconclusive or negative outcomes, emphasizing that it may be difficult to identify helpful information for individuals receiving an uncertain or negative result. There were few data from non-English speakers, highlighting the need to develop strategies to reach this population. CONCLUSION: Our study emphasizes the need for clinicians to provide accurate and comprehensible information to individuals from diverse populations after genetic testing.

Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms.

PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Incremental Value of Exercise ECG to Myocardial Perfusion Single-Photon Emission Computed Tomography for Prediction of Cardiac Events.

Background Both myocardial perfusion single-photon emission computed tomography (MPS) and exercise ECG (Ex-ECG) carry prognostic information in patients with stable chest pain. However, it is not fully understood if combining the findings of MPS and Ex-ECG improves risk prediction. Current guidelines no longer recommend Ex-ECG for diagnostic evaluation of chronic coronary syndrome, but Ex-ECG could still be of incremental prognostic importance. Methods and Results This study comprised 908 consecutive patients (age 63.3±9.4 years, 49% male) who performed MPS with Ex-ECG. Subjects were followed for 5 years. The end point was a composite of cardiovascular death, acute myocardial infarction, unstable angina, and unplanned percutaneous coronary intervention. National registry data and medical charts were used for end point allocation. Combining the findings of MPS and Ex-ECG resulted in concordant evidence of ischemia in 72 patients or absence of ischemia in 634 patients. Discordant results were found in 202 patients (MPS-/Ex-ECG+, n=126 and MPS+/Ex-ECG-, n=76). During follow-up, 95 events occurred. Annualized event rates significantly increased across groups (MPS-/Ex-ECG- =1.3%, MPS-/Ex-ECG+ =3.0%, MPS+/Ex-ECG- =5.1% and MPS+/Ex-ECG+ =8.0%). In multivariable analyses MPS was the strongest predictor regardless of Ex-ECG findings (MPS+/Ex-ECG-, hazard ratio [HR], 3.0, P=0.001 or MPS+/Ex-ECG+, HR,4.0, P<0.001). However, an abnormal Ex-ECG almost doubled the risk in subjects with normal MPS (MPS-/Ex-ECG+, HR, 1.9, P=0.04). Conclusions In patients with chronic coronary syndrome, combining the results from MPS and Ex-ECG led to improved risk prediction. Even though MPS is the stronger predictor, there is an incremental value of adding data from Ex-ECG to MPS, especially in patients with normal MPS.