Doubly-Ranked Stratification in Mendelian Randomization
Doubly-ranked (DR) stratification is a nonparametric, simple yet powerful method for instrument variable (IV) analysis and Mendelian randomization (MR) studies to create sub-groups, known as "strata", in which the IV assumption is satisfied. DR stratification can be applied in a wide range of IV or MR studies, including assessing homogeneity assumption, conducting nonlinear causal studies, and heterogeneous effects studies. The DRMR package can assist in generating stratifications, providing relevant results, and supporting further analysis based on stratification results.
This manuscript will demonstrate the fundamental concepts of DR stratification and provide a simple, step-by-step guide for applying this method. Subsequent papers will appear to provide further details and insights.1.
You can Install the DRMR package from Github with:
devtools::install_github("HDTian/DRMR")library(DRMR)Alternatively, you can also try the SUMnlmr2 package, where the DR method was embedded.
When examining potential non-linear causal effects, one approach is to divide the population into multiple subgroups or strata, each with varying levels of exposure. IV analysis can then be applied to each stratum, and the stratum-specific IV estimates can reveal the underlying shape of the causal effect. There are three main stratification methods:
| Naive stratification | Residual stratification3 | Doubly-ranked stratification4 | |
|---|---|---|---|
| Discription | Directly stratify on the exposure level. | First build the 'residual exposure' by regressing the exposure on the instrument and do the naive-style stratification on the residual values | First rank the instrument values to form pre-stratum, then rank the exposure values to form stratum (see schematic diagram below) |
| Potential Issues | The exposure is often the common effect of the instrument and the confounders. Therefore, stratifying or conditioning on the common effect may introduce collider bias5, and violate the exchangeability of the strata. | Residual stratification requires strong parametric assumptions; for exmaple, the linearity and homogeneity assumption of the instrument-exposure model |
Use the function getDat() to create a toy example, where you can experiment with different types of instruments (IVtype), instrument-exposure models (ZXmodel), and exposure-outcome models (XYmodel).
dat<-getDat( IVtype='cont', ZXmodel='C',XYmodel='2' )Draw the doubly-ranked stratification (use ?Stratify to check the parameters for stratification)
rdat<-Stratify(dat)
RES<-getSummaryInf(rdat)
head(RES$DRres)# size min 1q mean 3q max Fvalue bx bxse by byse est se target
#Stratum 1 1000 -14.635373 -8.665547 -7.374266 -6.053520 -1.1173800 69.95673 0.9898284 0.11834371 -1.4172479 0.16323707 -1.4318117 0.16491451 NA
#Stratum 2 1000 -12.093102 -6.755072 -5.666040 -4.554825 -1.0455971 159.92760 1.2086197 0.09557140 -1.3118679 0.10666678 -1.0854266 0.08825504 NA
#Stratum 3 1000 -9.489875 -5.611448 -4.575575 -3.524639 -0.3745066 241.20073 1.3153286 0.08469250 -1.2018580 0.08321997 -0.9137321 0.06326934 NA
#Stratum 4 1000 -8.000145 -4.732373 -3.720508 -2.668669 -0.2082876 306.00529 1.4035171 0.08023304 -1.0607026 0.07773271 -0.7557461 0.05538423 NA
#Stratum 5 1000 -7.260873 -3.926916 -2.943308 -1.926862 1.3822956 407.00318 1.5382303 0.07624695 -0.8423861 0.07007546 -0.5476333 0.04555590 NA
#Stratum 6 1000 -6.791493 -3.238730 -2.146673 -1.129673 2.9942412 453.88022 1.6360871 0.07679550 -0.6558742 0.06643903 -0.4008797 0.04060849 NAThe function Stratify() will return the individual stratification index. The function getSummaryInf() will provide summary information based on the stratified result.
Note that the naive and residual stratification can be regarded as special scenarios of the DR stratification. Hence, you may prefer to use only the DR method.
For naive stratification, it is equivalent to applying DR with one pre-stratum:
rdat<-Stratify(dat,SoP=nrow(dat))
getSummaryInf( rdat,onlyDR=TRUE)For residual stratification, it is equivalent to applying the naive stratification wrt the residual variables
dat$M<-resid(lm( dat$X~dat$Z )) #obtain the residual variables first
rdat<-Stratify(dat,SoP=nrow(dat),onExposure=FALSE)
getSummaryInf( rdat,onlyDR=TRUE)If you need to stratify on a covariate (which is common in many heterogeneous effect studies6), first define the covariate to be stratified by as M in dat, and then simply run the following code.
dat$M<-covarite_vector #added the covariate information
rdat<-Stratify(dat,onExposure=FALSE)
getSummaryInf( rdat)The coarsened exposure refers to the exposure measured with discrete values that are considered as an approximation for its latent continuous values. Such values could be rounded, binned into categories, or truncated, and all of them should satisfy the rank preserving condition7. The properties of such coarsened exposure enable the use of doubly-ranked stratification, but extra assessment for the degree of coarseness should be done before stratification. One way to do this is by calculating the Gelman-Rubin uniformity values of the rank index in each stratum. You can run the following code to perform this assessment.
getGRstats(rdat)
# Stratum GR_low GR_up maxGR
# "Stratum1" "1" "1.001" "1.001"
# "Stratum2" "1.001" "1" "1.001"
# "Stratum3" "1" "1" "1"
# ...
small values (<1.02) indicate a small degree of coarsenness.
The doubly-ranked stratification supports a wide variaty of instrument types, including dichotomous IV, discrete IV, high-dimensional IV, continuous IV, mixture IVs. For single IV, just denote its value by Z in dat. For high-dimensional IV, integrate them as a weighted score (e.g. the weigthed gene score in MR). For exmaple
dat$Z<-lm( dat$X~ dat$G1+ dat$G2 + ... )$fitted #G1 G2 ... are genetic variantsIf you outcome is not or cannot transoformed to a continous outcome with simple linear model, you may need use other models8. For exmaple, if you outcome is a binary, you can adjust the fitting model using the argument family_used
getSummaryInf( rdat,family_used='binomial')If you need to adjust for covariates, add them to your data dat or rdat with the name C1, C2, etc. Ensure that the data type is correct as the fitting will follow the rules of the lm function9. To enable covariate adjustment, set the argument covariate=TRUE.
getSummaryInf( rdat,covariate=TRUE)One feature of the stratification in the DRMR package is that the stratification function will not introduce randomness (in the sense that the same input data will always generate the same stratification results)10. This is beneficial in terms of transparency and reproducibility. However, since ties are broken at random for constant instrument or exposure values, the randomness of such breaks may be considered in some analysis. You can use the argument seed to create and track the randomness, For example:
Stratify(dat)
Stratify(dat,seed=1)
Stratify(dat,seed=2)You may consider transformed exposures or covariates11. The transformed variable could be helpful in terms of interpretation. If you use a bijective transformation, the DR stratification will not be changed. You can simply transform you variable wrt dat by using dat$X<-f(dat$X) where f() is your transformation function`
Smoothing12
There are several methods for smoothing the stratification estimation (the stratum-specific estimates are called LACE), including the fractional polynomial method and the piecewise linear method13.
To use the fractional polynomial method (e.g. with degree 2) with the doubly-ranked stratification, run
smooth_res<-Smooth(RES$DRres,Norder=3,baseline=0) #RES is the result returned by getSummaryInf()If you wish to visualize the results, simply run smooth_res$p or smooth_res$hp
To use the piecewise linear method with the doubly-ranked stratification, run:
cutting_values<-(RES$DRres$mean[-1] + head( RES$DRres$mean,-1) )/2
smooth_res<-Smooth(RES$DRres,Norder=1,baseline=0,Knots=cutting_values)The DRMR package follows a one-argument style, which means that in principle all you need to provide is a one-sample data frame. Before using the package, ensure that the input data is in the form of a dataframe:
is.data.frame(your_prepared_dat)
dat<-as.data.frame(your_prepared_dat)The DRMR package does not require you to specify instruments, exposures, or outcomes as arguments. The functions will automatically draw stratification and perform related analysis based on the column names of the inputted dataframe. It is important to ensure that the column names match the required naming conventions for the function to work properly.:
- The instrument:
Z(see the 'Different types of instrument' section if your instrument is complex) - The exposure:
X - The outcome:
Y - (if applicable) the covariate to stratify:
M - (if applicable) the covariate to adjust:
C1,C2,C3, ...
Check the names of your data frame
colnames(dat)Always be careful about the value type (e.g. for each variable do you need numeric values or character values?)
apply(dat, 2, is.numeric)
apply(dat, 2, is.character)Then clean your data (e.g. values modification, values rescale, imputation, removing missing data, etc)
Assume you now have the samples in a data frame dat with correctly named variables (Z, X, Y, etc.), you can simply run the following code:
rdat<-Stratify(dat)
RES<-getSummaryInf(rdat)
smooth_res<-Smooth(RES$DRres,Norder=3,baseline=0)then you can use the information in RES and smooth_res (try ?Stratify, ?getSummaryInf and ?Smooth to check the details) to build the results you desire14.
Footnotes
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Different papers would use different writing style for illustration and interpretation. Contact me if you are confused or interested in any aspect of the DR stratification method. ↩
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https://www.biorxiv.org/content/10.1101/2022.06.28.497930v1.abstract ↩
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https://link.springer.com/article/10.1007/s10654-022-00879-0 ↩
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See the Supplementary Text S2 of the origina doubly-ranked stratification paper ↩
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Some outcome types are tricky, contact me to discuss the most appropriate model ↩
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All character variables will be treated as factor variables, and corresponding dummy variables will be created to fit in
lm. If a continuous variable is in character form, it should be transformed into a numerical format before being used in the analysis. ↩ -
I considered whether to have the function perform break permutation automatically, but I decided against it as it might result in the user losing control over the variation of results caused by the randomness introduced internally (e.g., if they tend not to set a seed). Although these variations often do not affect any conclusions, I removed the randomness from inside the function to ensure transparency and reproducibility. ↩
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One example is the log-transformation: https://www.medrxiv.org/content/10.1101/2022.10.26.22280570v2 ↩
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The necessity of smoothing depends on the purpose of your study; if you are doing counterfactual prediction, smoothing is well worth trying; if you are doing inference, smoothing is usually not necessary. ↩
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https://onlinelibrary.wiley.com/doi/full/10.1002/gepi.22041 ↩
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Feel free to contact me if you have any further questions or need additional information that the current function cannot provide. I would be happy to discuss your study further and provide any assistance you may need. ↩