{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T15:27:41Z","timestamp":1781882861198,"version":"3.54.5"},"update-to":[{"DOI":"10.12688\/f1000research.26848.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000}}],"reference-count":32,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"\n Compound Heterozygous (\n CH<\/ns3:italic>\n )\n \n variant identification requires distinguishing maternally from paternally derived nucleotides, a process that requires numerous computational tools. Using such tools often introduces unforeseen challenges such as installation procedures that are operating-system specific, software dependencies that must be installed, and formatting requirements for input files. To overcome these challenges, we developed Compound Heterozygous Variant Identification Pipeline (CompoundHetVIP), which uses a single Docker image to encapsulate commonly used software tools for file aggregation (\n BCFtools<\/ns3:italic>\n or\n GATK4<\/ns3:italic>\n ), VCF liftover (\n Picard Tools<\/ns3:italic>\n ), joint-genotyping (\n GATK4<\/ns3:italic>\n ), file conversion (\n Plink2<\/ns3:italic>\n ), phasing (\n SHAPEIT2<\/ns3:italic>\n ,\n Beagle<\/ns3:italic>\n , and\/or\n Eagle2<\/ns3:italic>\n ), variant normalization (\n vt<\/ns3:italic>\n tools), annotation (\n SnpEff<\/ns3:italic>\n ), relational database generation (\n GEMINI<\/ns3:italic>\n ), and identification of\n CH<\/ns3:italic>\n , homozygous alternate, and\n de novo<\/ns3:italic>\n variants in a series of 13 steps. To begin using our tool, researchers need only install the Docker engine and download the CompoundHetVIP Docker image. The tools provided in CompoundHetVIP, subject to the limitations of the underlying software, can be applied to whole-genome, whole-exome, or targeted exome sequencing data of individual samples or trios (a child and both parents), using VCF or gVCF files as initial input. Each step of the pipeline produces an analysis-ready output file that can be further evaluated. To illustrate its use, we applied CompoundHetVIP to data from a publicly available Ashkenazim trio and identified two genes with a candidate\n CH<\/ns3:italic>\n variant and two genes with a candidate homozygous alternate variant after filtering based on user-set thresholds for global minor allele frequency, Combined Annotation Dependent Depletion, and Gene Damage Index. While this example uses genomic data from a healthy child, we anticipate that most researchers will use CompoundHetVIP to uncover missing heritability in human diseases and other phenotypes. CompoundHetVIP is open-source software and can be found at\n https:\/\/github.com\/dmiller903\/CompoundHetVIP<\/ns3:ext-link>\n ; this repository also provides detailed, step-by-step examples.\n <\/ns3:p>","DOI":"10.12688\/f1000research.26848.2","type":"journal-article","created":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T19:52:16Z","timestamp":1612986736000},"page":"1211","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["CompoundHetVIP: Compound Heterozygous Variant Identification Pipeline"],"prefix":"10.12688","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8387-9791","authenticated-orcid":false,"given":"Dustin B.","family":"Miller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.54440.r79307, Soohyun Lee, Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA, 24 Feb 2021, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/9-1211\/v2#referee-response-79307","order":0,"name":"referee-response-79307","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.29647.r76628, Sushant Patil, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA, 25 Jan 2021, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/9-1211\/v1#referee-response-76628","order":1,"name":"referee-response-76628","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Dustin Miller<\/b>; \nPosted: 02 Feb 2021<\/i>; Thank you for taking the time to review our manuscript. We appreciate your thorough and helpful comments. We have addressed these comments below in a point-by-point response. These changes have made the manuscript more informative and insightful. The reviewers comments are in regular font. Our responses are in \nbold<\/b>. 1. It appears that the program can only be used with whole-genome sequencing VCFs. Is that true? How about VCFs generated from WES or targeted panel? \nThank you for pointing this out. We designed this pipeline with WGS in mind and did not think about other types of next-gen data. To test the pipelines on WES\/targeted exome data, we ran the pipeline on a publicly available dataset available here: https:\/\/my.pgp-hms.org\/profile\/huF85C76. The data we used was the \u201cHelix Exome+ WES\u201d VCF file (https:\/\/my.pgp-hms.org\/user_file\/download\/3888). After filtering the data for positions that passed quality filters and had a quality > 20, we started on step 3 and went through all remaining steps. The pipeline worked well. We have made this more clear in the manuscript. <\/b> 2. Step 5 - "CompoundHetVIP can perform phasing using SHAPEIT2, Eagle210, and\/or Beagle9.". Is there a 'default' mode of execution for the software? If not, I suggest to have one and include one or all of these phasing programs as part of it.  \nWe have a separate script for all 3 phasing programs. That way the user can choose which program to use. Within each script, the phasing software is executed under default parameters. Our example PDF uses SHAPEIT2 and we recommend this as the default phaser to use, especially when using trio data. However, we feel that the choice of phasing program is fundamental to our pipeline and should require an explicit decision from the user; so we require the user to select one. We have made this more clear in the example documentation (https:\/\/github.com\/dmiller903\/CompoundHetVIP\/blob\/master\/CompoundHetVIP_example.pdf) and in the manuscript.<\/b> 3. In Figure 1, I recommend labeling each box with the corresponding Step # to relate it to the text in the manuscript.  \nThank you for the recommendation. We have updated the figure to show step numbers.<\/b> 4. Ideally all VCFs should be 1-based. In a hypothetical scenario, if the parents' VCFs are 0-based and the child's 1-based (coming from different workflows), will the program be able to detect and handle such discrepancy?  \nThis pipeline assumes input VCF files are 1-based. We added this disclaimer to the example documentation referenced in response 2. During step 11, GEMINI 0-bases the positions. However, during step 12, they are reverted back to 1-based positions for consistency. <\/b> 5. I recommend saying minor allele frequency (MAF) as Global minor allele frequency (MAF) at first instance. It is easy to be mistaken that for mutant allelic frequency in cancer genomics. \nThank you for this recommendation. We have updated the manuscript to say \u201cglobal minor allele frequency\u201d when first referenced.<\/b> \nIn addition to the changes mentioned above, we have made a few other changes we would like to mention here: <\/b> 1. We changed the way we filter the variants to be more simple but also more strict. Originally we allowed some variants to be considered if they were of \u201cHIGH\u201d putative impact but were missing CADD or MAF values. To obtain the variants most likely to play a role in disease, we made the requirement more strict. Now, CADD and MAF scores must be available for all variants, variants must be in exonic regions, and variants can have either \u201cMED\u201d or \u201cHIGH\u201d putative impact. Making these changes did not change the number of CH variants identified in the example dataset, but will likely have an effect in other datasets. This change in how variants are filtered may provide the users with a smaller subset of putative variants, but the CompoundHetVIP will provide more information for the users to use in downstream analysis (i.e. CADD and MAF values for all variants rather than just some of the variants). Our description of the filtering method has been updated in the manuscript.  2. There was an error in our script that identified homozygous alternate variants. Some of our previous code required that a gene have 2 variants in order to be written to the output file. This has been fixed, and it slightly changed the results. Originally we reported only 1 gene with a homozygous alternate variant in the example dataset. After updating the script and running it again, there are 2 genes that have a homozygous alternate variant. This result has been modified in the manuscript. 3. Minor updates to the example PDF (https:\/\/github.com\/dmiller903\/CompoundHetVIP\/blob\/master\/CompoundHetVIP_example.pdf) were made for added clarity and explanation.","URL":"https:\/\/f1000research.com\/articles\/9-1211\/v2#referee-comment-6334","order":2,"name":"referee-comment-6334","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}