A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes

Optimal classification of the response to lithium (Li) is crucial in genetic and biomarker research. This proof of concept study aims at exploring whether different approaches to phenotyping the response to Li may influence the likelihood of detecting associations between the response and genetic ma...

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Autores principales:	Jan Scott, Mohamed Lajnef, Romain Icick, Frank Bellivier, Cynthia Marie-Claire, Bruno Etain
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	bipolar disorder lithium response phenotype genetics circadian genes Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/433557f612634685af2645eb7eeb9972
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spelling	oai:doaj.org-article:433557f612634685af2645eb7eeb99722021-11-25T18:39:06ZA Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes10.3390/ph141110721424-8247https://doaj.org/article/433557f612634685af2645eb7eeb99722021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1072https://doaj.org/toc/1424-8247Optimal classification of the response to lithium (Li) is crucial in genetic and biomarker research. This proof of concept study aims at exploring whether different approaches to phenotyping the response to Li may influence the likelihood of detecting associations between the response and genetic markers. We operationalized Li response phenotypes using the Retrospective Assessment of Response to Lithium Scale (i.e., the Alda scale) in a sample of 164 cases with bipolar disorder (BD). Three phenotypes were defined using the established approaches, whilst two phenotypes were generated by machine learning algorithms. We examined whether these five different Li response phenotypes showed different levels of statistically significant associations with polymorphisms of three candidate circadian genes (<i>RORA</i>, <i>TIMELESS</i> and <i>PPARGC1A</i>), which were selected for this study because they were plausibly linked with the response to Li. The three original and two revised Alda ratings showed low levels of discordance (misclassification rates: 8–12%). However, the significance of associations with circadian genes differed when examining previously recommended categorical and continuous phenotypes versus machine-learning derived phenotypes. Findings using machine learning approaches identified more putative signals of the Li response. Established approaches to Li response phenotyping are easy to use but may lead to a significant loss of data (excluding partial responders) due to recent attempts to improve the reliability of the original rating system. While machine learning approaches require additional modeling to generate Li response phenotypes, they may offer a more nuanced approach, which, in turn, would enhance the probability of identifying significant signals in genetic studies.Jan ScottMohamed LajnefRomain IcickFrank BellivierCynthia Marie-ClaireBruno EtainMDPI AGarticlebipolar disorderlithiumresponsephenotypegeneticscircadian genesMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1072, p 1072 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	bipolar disorder lithium response phenotype genetics circadian genes Medicine R Pharmacy and materia medica RS1-441
spellingShingle	bipolar disorder lithium response phenotype genetics circadian genes Medicine R Pharmacy and materia medica RS1-441 Jan Scott Mohamed Lajnef Romain Icick Frank Bellivier Cynthia Marie-Claire Bruno Etain A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes
description	Optimal classification of the response to lithium (Li) is crucial in genetic and biomarker research. This proof of concept study aims at exploring whether different approaches to phenotyping the response to Li may influence the likelihood of detecting associations between the response and genetic markers. We operationalized Li response phenotypes using the Retrospective Assessment of Response to Lithium Scale (i.e., the Alda scale) in a sample of 164 cases with bipolar disorder (BD). Three phenotypes were defined using the established approaches, whilst two phenotypes were generated by machine learning algorithms. We examined whether these five different Li response phenotypes showed different levels of statistically significant associations with polymorphisms of three candidate circadian genes (<i>RORA</i>, <i>TIMELESS</i> and <i>PPARGC1A</i>), which were selected for this study because they were plausibly linked with the response to Li. The three original and two revised Alda ratings showed low levels of discordance (misclassification rates: 8–12%). However, the significance of associations with circadian genes differed when examining previously recommended categorical and continuous phenotypes versus machine-learning derived phenotypes. Findings using machine learning approaches identified more putative signals of the Li response. Established approaches to Li response phenotyping are easy to use but may lead to a significant loss of data (excluding partial responders) due to recent attempts to improve the reliability of the original rating system. While machine learning approaches require additional modeling to generate Li response phenotypes, they may offer a more nuanced approach, which, in turn, would enhance the probability of identifying significant signals in genetic studies.
format	article
author	Jan Scott Mohamed Lajnef Romain Icick Frank Bellivier Cynthia Marie-Claire Bruno Etain
author_facet	Jan Scott Mohamed Lajnef Romain Icick Frank Bellivier Cynthia Marie-Claire Bruno Etain
author_sort	Jan Scott
title	A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes
title_short	A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes
title_full	A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes
title_fullStr	A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes
title_full_unstemmed	A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes
title_sort	comparison of different approaches to clinical phenotyping of lithium response: a proof of principle study employing genetic variants of three candidate circadian genes
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/433557f612634685af2645eb7eeb9972
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A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes

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