Rare Variants in Inborn Errors of Immunity Genes Associated With Covid-19 Severity

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1. Version published to 10.3389/fcimb.2022.888582

   May 27, 2022
2. 

   ScreenIT

   Mar 15, 2022

   SciScore for 10.1101/2022.03.09.22270766: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   NIH rigor criteria are not applicable to paper type.

   Table 2: Resources

   Software and Algorithms
   Sentences	Resources
   We used PLINK 2.0 (Chang et al. 2015) to infer sex of individuals from SNP genotypes and VerifyBamID (F. Zhang et al. 2020) to assess the level of DNA contamination.	PLINK suggested: (PLINK, RRID:SCR_001757)
   To increase the average depth of study, sequence fastq files of each patient were merged together to generate one GVCF file by BWA and Sentieon Genomics software (Freed et al. 2017).	BWA suggested: (BWA, RRID:SCR_010910)
   After the application of excessHet (<54.69) filter, Variant Quality Score Recalibration (VQSR) was completed by using the Genome Analysis Toolkit (GATK version 4.1.2) …

   SciScore for 10.1101/2022.03.09.22270766: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   NIH rigor criteria are not applicable to paper type.

   Table 2: Resources

   Software and Algorithms
   Sentences	Resources
   We used PLINK 2.0 (Chang et al. 2015) to infer sex of individuals from SNP genotypes and VerifyBamID (F. Zhang et al. 2020) to assess the level of DNA contamination.	PLINK suggested: (PLINK, RRID:SCR_001757)
   To increase the average depth of study, sequence fastq files of each patient were merged together to generate one GVCF file by BWA and Sentieon Genomics software (Freed et al. 2017).	BWA suggested: (BWA, RRID:SCR_010910)
   After the application of excessHet (<54.69) filter, Variant Quality Score Recalibration (VQSR) was completed by using the Genome Analysis Toolkit (GATK version 4.1.2) (DePristo et al. 2011).	Genome Analysis Toolkit suggested: None GATK suggested: (GATK, RRID:SCR_001876)
   To improve the genotyping accuracy, we used the Beagle 4.0 software (Browning and Browning 2016) to perform LD-based genotype refinement by taking genotype likelihoods as inputs.	Beagle suggested: (BEAGLE, RRID:SCR_001789)
   Functional Annotation: We annotated rare variants (MAF < 0.5%) in our final call set by using the Ensembl Variant Effect Predictor (VEP, build 103,	Ensembl Variant Effect Predictor suggested: None Variant suggested: (VARIANT, RRID:SCR_005194)
   The databases for annotation included dbSNP (Sherry et al. 2001), gnomAD (Karczewski et al. 2020), and 1000 Genomes Project (Clarke et al. 2012).	dbSNP suggested: (dbSNP, RRID:SCR_002338) 1000 Genomes Project suggested: (1000 Genomes Project and AWS, RRID:SCR_008801)
   Missense variants with CADD score > MSC (Mutation Significance Cut-off) score (95% confidence interval) (Itan et al. 2016) were predicted as likely-deleterious missense variants.	Mutation Significance Cut-off suggested: None
   Rare Variants Analyses: To investigate the cumulative effects of multiple rare variants, we performed gene-based association analysis using KGGSeq 1.0 (Li et al. 2017) with the sequence kernel association test (SKAT) (M. C. Wu et al. 2010), the Optimized SKAT (SKAT-O) (Lee, Wu, and Lin 2012), and Burden test.	KGGSeq suggested: (KGGSeq, RRID:SCR_005311)
   We further carried out pathway-based analysis by testing the Kyoto Encyclopedia of Genes and Genomes (KEGG) gene sets (Kanehisa and Goto 2000).	KEGG suggested: (KEGG, RRID:SCR_012773)
   The mutation accuracy of variants in these 148 candidate genes (one overlap between 13 IFN-genes and 136 HGI-genes) was manually checked by using Samtools 1.10 (Danecek et al. 2021).	Samtools suggested: (SAMTOOLS, RRID:SCR_002105)
   We used the STRING version 10.5 (Search Tool for the Retrieval of Interacting Genes/Proteins) (Szklarczyk et al. 2019) to build the PPI network.	STRING suggested: (STRING, RRID:SCR_005223)

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   Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

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   Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

   Despite the many compelling and significant findings of our work, there are still a few limitations to be noted. First, the sample size we used is relatively small, and the limited sample size limits the statistical power for identifying rare variants. More studies with large sample sizes are demanded to validate our results and uncover more candidate variants. Second, even though our work has suggested several candidate genes and pathways potentially related to Covid-19 severity, the true underlying genetic mechanisms of how they affect disease progression need to be explored by more persuasive experimental designs. Covid-19 is assessed as a complex infectious disease and affected many risk factors. Symptoms of Covid-19 are highly variable, ranging from unnoticeable to severe and even death. The host genetic background is only partly responsible for the phenotypic heterogeneity. In recent years, multi-omics studies have proven a powerful and successful strategy to provide a broader perspective in understanding disease development and biological phenomena. Several multi-omics analyses of Covid-19 have been proposed to integrate multiple “omes” data to unravel disease mechanisms at multiple omics levels (Overmyer et al. 2021; Su et al. 2020; Montaldo et al. 2021; P. Wu, Chen, et al. 2021; Stephenson et al. 2021). The integrative analyses of rare genome and other “omes” data (e.g., proteome, transcriptome, epigenome, metabolome, and microbiome) may inspire us to discover new ri...

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   Results from TrialIdentifier: No clinical trial numbers were referenced.

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   Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

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   Results from JetFighter: We did not find any issues relating to colormaps.

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   Results from rtransparent:

   • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
   • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
   • No protocol registration statement was detected.

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   Results from scite Reference Check: We found no unreliable references.

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3. 

   Version published to 10.1101/2022.03.09.22270766 on medRxiv

   Mar 12, 2022