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. 2022 Sep 20;80(12):1115-1126.
doi: 10.1016/j.jacc.2022.06.040.

Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy

Luis Escobar-Lopez  1 , Juan Pablo Ochoa  2 , Ana Royuela  3 , Job A J Verdonschot  4 , Matteo Dal Ferro  5 , Maria Angeles Espinosa  6 , Maria Sabater-Molina  7 , Maria Gallego-Delgado  8 , Jose M Larrañaga-Moreira  9 , Jose M Garcia-Pinilla  10 , Maria Teresa Basurte-Elorz  11 , José F Rodríguez-Palomares  12 , Vicente Climent  13 , Francisco J Bermudez-Jimenez  14 , María Victoria Mogollón-Jiménez  15 , Javier Lopez  16 , Maria Luisa Peña-Peña  17 , Ana Garcia-Alvarez  18 , Bernardo López-Abel  19 , Tomas Ripoll-Vera  20 , Julian Palomino-Doza  21 , Antoni Bayes-Genis  22 , Ramon Brugada  23 , Uxua Idiazabal  24 , Jesus G Mirelis  1 , Fernando Dominguez  1 , Michiel T H M Henkens  25 , Ingrid P C Krapels  4 , Han G Brunner  26 , Alessia Paldino  5 , Denise Zaffalon  5 , Luisa Mestroni  27 , Gianfranco Sinagra  5 , Stephane R B Heymans  28 , Marco Merlo  5 , Pablo Garcia-Pavia  29
Affiliations

Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy

Luis Escobar-Lopez et al. J Am Coll Cardiol. .

Abstract

Background: Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption.

Objectives: This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD.

Methods: Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries.

Results: A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78).

Conclusions: The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD.

Keywords: dilated cardiomyopathy; genetic variant; genetics; genotype; predictor.

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Conflict of interest statement

Funding Support and Author Disclosures This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) (PI17/01941, PI18/0004, PI19/01283, PI20/0320) (co-funded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). The CNIC is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). This study was also supported by the Netherlands Cardiovascular Research Initiative, an initiative with support from the Dutch Heart Foundation, DCVA Double Dosis 2020B005. The Hospital Universitario Puerta de Hierro, the Hospital Universitario Virgen de la Arrixaca and the Azienda Sanitaria Universitaria Giuliano-Isontina are members of the European Reference Network for rare, low-prevalence, and complex diseases of the heart (ERN GUARD-Heart). Dr Ochoa is an employee of Health in Code. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

FIGURE 1
FIGURE 1. Apparent Performance and Internal Validation by Bootstrapping of the Model
Calibration plot assessing the apparent predictive performance of the model in the derivation cohort (top). Data points are mean predicted against mean observed frequencies of a positive genetic test result. The dashed blue line represents the line of equality. Internal validation by bootstrapping (bottom) showed good agreement between predicted (x-axis) and observed (y-axis) events (Gen+). Blue circles represent binned logistic regression estimates with 95% confidence for quintiles of the predicted outcome. The straight line is the continuous calibration (hazard regression). The dashed line represents perfect calibration. Red diamonds in the upper x-axis reflect the number of Gen— patients with a predicted outcome corresponding to the x-axis value, and blue circles in the lower x-axis reflect the number of patients with a positive genetic test result with a predicted outcome corresponding to the x-axis value.
FIGURE 2
FIGURE 2. Yield of Positive Genetic Test Result According to Score Value
Percentage of observed individuals with a positive genetic test result in the derivation (blue bars) and validation (red bars) cohorts. *None of the patients in the validation cohort scored 5 points.
CENTRAL ILLUSTRATION
CENTRAL ILLUSTRATION. Components, Validation, and Performance of the Madrid Genotype Score
(Top left) Components of the Madrid Genotype Score and points attributed to each parameter. (Top right) Increase in the yield of positive genetic testing results according to increased score category of the Madrid Genotype Score. (Bottom left) Positive genetic testing result according to cumulative score threshold from ≥0 to ≥4 points of the Madrid Genotype Score. (Bottom right) Internal and external validation of the score showed a good overall agreement between the predicted and observed rate of a positive genetic testing result. DCM = dilated cardiomyopathy; ECG = electrocardiography; LBBB = left bundle branch block.
See this image and copyright information in PMC

Comment in

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