Haplotype Trend Regression with eXtra flexibility (HTRX)

This is the location for the HTRX tool that was firstly proposed by Barrie, W., Yang, Y., Irving-Pease, E.K. et al. Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Nature 625, 321–328 (2024).
and then illustrated in detail by
Yang Y, Lawson DJ. HTRX: an R package for learning non-contiguous haplotypes associated with a phenotype. Bioinformatics Advances 3.1 (2023): vbad038.


Haplotype Trend Regression with eXtra flexibility (HTRX) searches a pre-defined set of SNPs for haplotype patterns that include single nucleotide polymorphisms (SNPs) and non-contiguous haplotypes.

We search over all possible templates which give a value for each SNP being ‘0’ or ‘1’, reflecting whether the reference allele of each SNP is present or absent, or an ‘X’ meaning either value is allowed.

We used a two-stage procedure to select the best HTRX model (function “do_cv”).
Stage 1: select candidate models;
Stage 2: select the best model using 10-fold cross-validation.

Longer haplotypes are important for discovering interactions. However, there are \(3^k-1\) haplotypes in HTRX if the region contains \(k\) SNPs, making it unrealistic for regions with large numbers of SNPs. To address this issue, we proposed “cumulative HTRX” (function “do_cumulative_htrx”) that enables HTRX to run on longer haplotypes, i.e. haplotypes which include at least 7 SNPs (we recommend). Besides, we provide a parameter “max_int” which controls the maximum number of SNPs that can interact.

Install R package “HTRX”


This package is also available from CRAN. You can install it by



A tutorial of package HTRX can be found in vignettes/HTRX_vignette.pdf



## use dataset "example_hap1", "example_hap2" and "example_data_nosnp"
## "example_hap1" and "example_hap2" are both genomes of 8 SNPs for 5,000 individuals (diploid data) 
## "example_data_nosnp" is an example dataset which contains the outcome (binary), sex, age and 18 PCs

## visualise the covariates data

## visualise the genotype data for the first genome

## we perform HTRX on the first 4 SNPs
## we first generate all the haplotype data, as defined by HTRX

## If the data is haploid, please set
## HTRX_matrix=make_htrx(HTRX::example_hap1[,1:4],HTRX::example_hap1[,1:4])

## next compute the maximum number of independent features

## then perform HTRX using 2-step cross-validation
## to compute additional variance explained by haplotypes
## If you want to compute total variance explained, please set gain=FALSE
htrx_results <- do_cv(HTRX::example_data_nosnp,

## If we want to compute the total variance explained
## we can set gain=FALSE in the above example

## we perform cumulative HTRX on all the 8 SNPs using 2-step cross-validation
## to compute additional variance explained by haplotypes
## If the data is haploid, please set hap2=HTRX::example_hap1
## If you want to compute total variance explained, please set gain=FALSE
## For Linux/MAC users, we strongly encourage you to set runparallel=TRUE
cumu_htrx_results <- do_cumulative_htrx(data_nosnp=HTRX::example_data_nosnp,