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A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups

Phenotype Prediction Scores (PPS) might be powerful tools to predict traits or the efficacy of treatments based on combinations of Single-Nucleotide Polymorphism (SNPs) in large samples. We developed a novel method to produce PPS models for small samples sizes. The set of SNPs is first filtered on t...

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Autores principales: Höhle, Daniël, van Rooij, Kim, Bloemers, Jos, Pfaus, James G., Michiels, Frits, Janssen, Paddy, Claassen, Eric, Tuiten, Adriaan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935233/
https://www.ncbi.nlm.nih.gov/pubmed/33667227
http://dx.doi.org/10.1371/journal.pone.0246828
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author Höhle, Daniël
van Rooij, Kim
Bloemers, Jos
Pfaus, James G.
Michiels, Frits
Janssen, Paddy
Claassen, Eric
Tuiten, Adriaan
author_facet Höhle, Daniël
van Rooij, Kim
Bloemers, Jos
Pfaus, James G.
Michiels, Frits
Janssen, Paddy
Claassen, Eric
Tuiten, Adriaan
author_sort Höhle, Daniël
collection PubMed
description Phenotype Prediction Scores (PPS) might be powerful tools to predict traits or the efficacy of treatments based on combinations of Single-Nucleotide Polymorphism (SNPs) in large samples. We developed a novel method to produce PPS models for small samples sizes. The set of SNPs is first filtered on those known to be relevant in biological pathways involved in a clinical condition, and then further filtered repeatedly in a survival strategy to select stabile positive/negative risk alleles. This method is applied on Female Sexual Interest/Arousal Disorder (FSIAD), for which two subtypes has been proposed: 1) a relatively insensitive excitatory system in the brain for sexual cues, and 2) a dysfunctional activation of brain mechanisms for sexual inhibition. A double-blind, randomized, placebo-controlled cross-over experiment was conducted on 129 women with FSIAD. The women received three different on-demand drug-combination treatments during 3 two-week periods: testosterone (0.5 mg) + sildenafil (50 mg), testosterone (0.5 mg) + buspirone (10 mg), or matching placebos. The resulted PPS were independently validated on patient-level and group-level. The AUC scores for T+S of the derivation set was 0.867 (95% CI = 0.796–0.939; p<0.001) and was 0.890 (95% CI = 0.778–1.000; p<0.001) on the validation set. For T+B the AUC of the derivation set was 0.957 (95% CI = 0.921–0.992; p<0.001) and 0.869 (95% CI = 0.746–0.992; p<0.001) for the validation set. Both formulas could reliably predict for each drug who benefit from the on-demand drugs and could therefore be useful in clinical practice.
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spelling pubmed-79352332021-03-15 A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups Höhle, Daniël van Rooij, Kim Bloemers, Jos Pfaus, James G. Michiels, Frits Janssen, Paddy Claassen, Eric Tuiten, Adriaan PLoS One Research Article Phenotype Prediction Scores (PPS) might be powerful tools to predict traits or the efficacy of treatments based on combinations of Single-Nucleotide Polymorphism (SNPs) in large samples. We developed a novel method to produce PPS models for small samples sizes. The set of SNPs is first filtered on those known to be relevant in biological pathways involved in a clinical condition, and then further filtered repeatedly in a survival strategy to select stabile positive/negative risk alleles. This method is applied on Female Sexual Interest/Arousal Disorder (FSIAD), for which two subtypes has been proposed: 1) a relatively insensitive excitatory system in the brain for sexual cues, and 2) a dysfunctional activation of brain mechanisms for sexual inhibition. A double-blind, randomized, placebo-controlled cross-over experiment was conducted on 129 women with FSIAD. The women received three different on-demand drug-combination treatments during 3 two-week periods: testosterone (0.5 mg) + sildenafil (50 mg), testosterone (0.5 mg) + buspirone (10 mg), or matching placebos. The resulted PPS were independently validated on patient-level and group-level. The AUC scores for T+S of the derivation set was 0.867 (95% CI = 0.796–0.939; p<0.001) and was 0.890 (95% CI = 0.778–1.000; p<0.001) on the validation set. For T+B the AUC of the derivation set was 0.957 (95% CI = 0.921–0.992; p<0.001) and 0.869 (95% CI = 0.746–0.992; p<0.001) for the validation set. Both formulas could reliably predict for each drug who benefit from the on-demand drugs and could therefore be useful in clinical practice. Public Library of Science 2021-03-05 /pmc/articles/PMC7935233/ /pubmed/33667227 http://dx.doi.org/10.1371/journal.pone.0246828 Text en © 2021 Höhle et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Höhle, Daniël
van Rooij, Kim
Bloemers, Jos
Pfaus, James G.
Michiels, Frits
Janssen, Paddy
Claassen, Eric
Tuiten, Adriaan
A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups
title A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups
title_full A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups
title_fullStr A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups
title_full_unstemmed A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups
title_short A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups
title_sort survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935233/
https://www.ncbi.nlm.nih.gov/pubmed/33667227
http://dx.doi.org/10.1371/journal.pone.0246828
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