Abstract

Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. Here, we report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We find heterogeneity in current research practices and a reporting bias toward certain diseases. Moreover, we identified 663 CNS cell‐derived phenotypes from 243 patients and 214 controls, which varied by mutation type and developmental stage in vitro. We clustered these phenotypes into a taxonomy and characterized these phenotype–genotype relationships to generate a phenogenetic map that revealed novel correlations among previously unrelated genes. We also find that alterations in patient‐derived molecular profiles associated with cellular phenotypes, and dysregulated genes show predominant expression in brain regions with pathology. Last, we developed the iPS cell phenogenetic map project atlas (iPhemap), an open submission, online database to continually catalog disease phenotypes. Overall, our findings offer new insights into the phenogenetics of iPSC‐derived models while our web tool provides a platform for researchers to query and deposit phenotypic information of neurological diseases.

Highlights

  • Disease modeling with induced pluripotent stem cells is creating an abundance of phenotypic information that has become difficult to follow and interpret

  • We determined that 67% of the studies focused on the investigation of neurodegenerative diseases and within this disease group, we found that diseases with well-characterized somatic mutations were more frequently reported, including Parkinson’s disease (29%), amyotrophic lateral sclerosis (ALS) (18%), Huntington’s disease (16%), Alzheimer’s disease (11%), frontotemporal dementia (FTD) (10%), and spinal muscular atrophy (SMA) (8%), Comparably, we noticed that a large number of the articles modeling neurodevelopmental diseases (30%) studied Rett syndrome (18%) (Fig 1A)

  • We posit that a retrospective analysis, like a mid-term examination, 10 years after the discovery of induced pluripotent stem cells (iPSCs), is needed to improve the reproducibility of the field, especially as we are investigating the role of genetic variation, such as single nucleotide polymorphisms (SNPs), in genomewide association studies (GWAS) (Sweet, 2017) of in vitro iPSC phenotypes using multiple patients

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Summary

Introduction

Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. We report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We identified 663 CNS cell-derived phenotypes from 243 patients and 214 controls, which varied by mutation type and developmental stage in vitro. We clustered these phenotypes into a taxonomy and characterized these phenotype–genotype relationships to generate a phenogenetic map that revealed novel correlations among previously unrelated genes. Our findings offer new insights into the phenogenetics of iPSC-derived models while our web tool provides a platform for researchers to query and deposit phenotypic information of neurological diseases

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