Variante effect predictor assessment pipeline

This GitHub repository contains the computational analysis pipeline used in the manuscript "Assessing computational variant effect predictors with a large prospective cohort" (in preparation).

Please note, this repository does NOT contain raw data from the UK Biobank as they are available upon application. Please visit the UK Biobank website to apply for data access.

Install

To install the pipeline, first make sure your R version is at least R 4.0. You can check by typing the following into your R console:

R.version()$major

Next, clone the repository by typing the following into your command line interface:

git clone https://github.com/kvnkuang/variant-effect-predictor-assessment

You need to download VARITY predictions (http://varity.varianteffect.org/downloads/varity_all_predictions.tar.gz), unzip the file (varity_all_predictions.txt) and move it to the common folder.

You also need access to UK Biobank exome variants (in pVCF format): https://biobank.ndph.ox.ac.uk/ukb/field.cgi?id=23148

Confiugre the running parameters

The config.yaml file lists all the running parameters that you can congifure.

Here we document all parameters supported by the pipeline and their functions.

Parameter	Description	Default Value
gene_list	A file with all the genes used in the study. See the sample file referred to by the default value for format.	common/genes.csv
phenotype_list	A file with all phenotypes (traits) used in the study. See the sample file referred to by the default value for format.	common/phenotypeDescriptions.csv
rscript_path	The path to the RScript executable.	Rscript
input_var_dir	The path to the input variants.	input
occurance_cutoff	The occurance cutoff used in the study. See the Material & Method section of the manuscript for detail.	10
bootstrap_iterations	The number of iterations for the bootstrap resampling process. See the Material & Method section of the manuscript for detail.	1000
all_variants_path	The filename pattern of the input variant files.	ukb23148_c%s_b%s_v1_filtered_mut.csv
unique_variants_path	The filename pattern of the input unique variants and computational predictor scores.	ukb23148_c%s_b%s_v1_all_weights.csv
variant_blocks_path	The filename of the pVCF file blocks. For ease of handling the pVCF formatted information for the exome genetics was split across a number of files. This document itemises the content of these files. Read more about this here: https://biobank.ctsu.ox.ac.uk/crystal/refer.cgi?id=837	common/pvcf_blocks.txt
withdraw_eids_path	A file with all the participants who have withdrawn their participation in the UK Biobank. See the sample file referred to by the default value for format. Replace "<withdrawn_eidx>" in the sample file with actual EIDs. We are unable to provide real EIDs due to UK Biobank's data sharing restrictions.	common/withdraws.csv
db_connect_path	A file with connection credentials to a local database where all UK Biobank variants are stored. See the sample file referred to by the default value for format. We are unable to provide access to the real database, but please see below ("Set up UK Biobank database") for the database schema that you can use to set up the database yourself with UK Biobank data.	db_connect.yaml
variant_predictors	A list of variant effect predictors used in the study. Format: [predictor name]: [predictor column name in unique variants file (unique_variants_path)]	!incomplete list! VARITY: VARITY_R_LOO_LOO PolyPhen-2: Polyphen2_selected_HVAR_score ...
plot_individual_correlations	Whetherindividually plot correlations as scatterplots	FALSE
plot_individual_correlations	Whetherindividually plot correlations as scatterplots	FALSE

Set up a local UK Biobank phenotype database

Using the phenotypes requested from the UK Biobank, set up a local UK Biobank phenotype database that the pipeline can use to query relevant phenotype information.

Please note, we are not permitted to provide any access to a database containing UK Biobank data. Instead, we provide this Data Definition Language (DDL) snippet that can be used to set up a database compatible with this analysis pipeline.

This snippnet is tested for MariaDB version 5.5 and should work for any modern MySQL and MariaDB instances.

create table phenotypes
(
	eid varchar(10) null,
	pid varchar(50) null,
	measurement text null,
	array_index smallint null
);

create index phenotype_pid_index
	on phenotypes (pid);

create index phenotypes_eid_index
	on phenotypes (eid);

create index phenotypes_eid_pid_index
	on phenotypes (eid, pid);

Here we describe the four columns defined in the above DDL snippet.

Column Name	Description
eid	The unique ID assigned to each UK Biobank participant
pid	The unique ID assigned to each phenotype (trait) in the UK Biobank. This must match with the field_ids in phenotype files defined in the config file above.
measurement	The actual measurement of the phenotype.
array_index	When a phenotype has multiple measurements, this index records the position of each measurement.

Run the pipeline

To run the pipeline, type the following line into your command line interface:

Rscript main.R <configuration-file> <log-dir>

There are two required arguments:

1. configuration-file: the path to configuration file (e.g. config.yaml)
2. log-dir: the directory to the log files (e.g. logs/)

Output

All output should be stored in the output folder.

In addition, a pval.csv is created in the root folder containing all pairwise predictor comparisons. The pval.csv included in this repository was generated from the benchmark described in the manuscript.

Contact us

If you have any feedback, suggestions or questions, please reach out via email or open an issue on github.