# A user’s guide to standard covariate measurement error correction for R

## Introduction

mecor is an R package for Measurement Error CORrection. mecor implements measurement error correction methods for linear models with continuous outcomes. The measurement error can either occur in a continuous covariate or in the continuous outcome. This vignette discusses covariate measurement error correction by means of standard regression calibration in mecor.

Regression calibration is one of the most popular measurement error correction methods for covariate measurement error. This vignette shows how standard regression calibration is applied in an internal validation study, a replicates study, a calibration study and an external validation study. Each of the four studies will be introduced in the subsequent sections, along with examples of how standard regression calibration can be applied in each of the four studies using mecor’s function mecor(). In all four studies, our interest lies in estimating the association between a continuous reference exposure $$X$$ and a continuous outcome $$Y$$, given covariates $$Z$$. Instead of $$X$$, the substitute error-prone exposure $$X^*$$ is measured.

## Internal validation study

The simulated data set vat in mecor is an internal covariate-validation study. An internal validation study includes a subset of individuals of whom the reference exposure $$X$$ is observed. The data set vat contains 1000 observations of the outcome insulin resistance $$IR_{ln}$$, the error-prone exposure waist circumference $$WC$$ and the covariates sex, age and total body fat, $$sex$$, $$age$$ and $$TBF$$, respectively. The reference exposure visceral adipose tissue $$VAT$$ is observed in approximately 25% of the individuals in the study.

# load internal covariate validation study
data("vat", package = "mecor")
#>         ir_ln         wc sex age        tbf       vat
#> 1 -0.09341837 -1.3136816   1  48 -0.6571345        NA
#> 2  0.16820894 -2.0336624   0  54 -1.5882163        NA
#> 3  0.57299976 -0.2611214   0  46 -1.1033709        NA
#> 4  0.63677178  0.8631987   0  55 -1.4785869 0.5083247
#> 5  0.92908882 -1.2054861   1  61  0.9020136        NA
#> 6 -0.72410039 -2.5032852   1  47 -0.9584166        NA

When ignoring the measurement error in $$WC$$, one would naively regress $$WC$$ and $$sex$$, $$age$$ and $$TBF$$ on $$IR_{ln}$$. This results in a biased estimation of the exposure-outcome association:

# naive estimate of the exposure-outcome association
lm(ir_ln ~ wc + sex + age + tbf, data = vat)
#>
#> Call:
#> lm(formula = ir_ln ~ wc + sex + age + tbf, data = vat)
#>
#> Coefficients:
#> (Intercept)           wc          sex          age          tbf
#>     0.50976      0.09697     -0.70953      0.01133      0.38783

Alternatively, one could perform an analysis restricted to the internal validation set:

# analysis restricted to the internal validation set
lm(ir_ln ~ vat + sex + age + tbf, data = subset(vat, !is.na(vat)))
#>
#> Call:
#> lm(formula = ir_ln ~ vat + sex + age + tbf, data = subset(vat,
#>     !is.na(vat)))
#>
#> Coefficients:
#> (Intercept)          vat          sex          age          tbf
#>    0.542422     0.195751    -0.450991     0.008737     0.291963

Although the above would result in an unbiased estimation of the exposure-outcome association, approximately 75% of the data is thrown out. Instead of doing an analysis restricted to the internal validation set, you could use standard regression calibration to correct for the measurement error in $$X^*$$. The following code chunk shows standard regression calibration with mecor():

mecor(formula = ir_ln ~ MeasError(substitute = wc, reference = vat) + sex + age + tbf,
data = vat,
method = "standard", # defaults to "standard"
B = 0) # defaults to 0
#>
#> Call:
#> mecor(formula = ir_ln ~ MeasError(substitute = wc, reference = vat) +
#>     sex + age + tbf, data = vat, method = "standard", B = 0)
#>
#> Coefficients Corrected Model:
#>  (Intercept)          vat          sex          age          tbf
#>  0.473398350  0.207598087 -0.438453038  0.009477677  0.270864391
#>
#> Coefficients Uncorrected Model:
#> (Intercept)          wc         sex         age         tbf
#>  0.50976395  0.09697045 -0.70952736  0.01132712  0.38782671

As shown in the above code chunk, the mecor() function needs a formula argument, a data argument, a method argument and a B argument. Presumably, you are familiar with the structure of a formula in R. The only thing that’s different here is the use of a MeasError() object in the formula. A MeasError() object is used to declare the substitute measure, in our case $$WC$$, and the reference measure, in our case $$VAT$$. The B argument of mecor() is used to calculate bootstrap confidence intervals for the corrected coefficients of the model. Let us construct 95% confidence intervals using the bootstrap with 999 replicates:

# save corrected fit
rc_fit <-
mecor(formula = ir_ln ~ MeasError(substitute = wc, reference = vat) + age + sex + tbf,
data = vat,
method = "standard", # defaults to "standard"
B = 999) # defaults to 0

Print the confidence intervals to the console using summary():

summary(rc_fit)
#>
#> Call:
#> mecor(formula = ir_ln ~ MeasError(substitute = wc, reference = vat) +
#>     age + sex + tbf, data = vat, method = "standard", B = 999)
#>
#> Coefficients Corrected Model:
#>              Estimate       SE SE (btstr)
#> (Intercept)  0.473398 0.146766   0.128033
#> vat          0.207598 0.034210   0.034857
#> age          0.009478 0.002598   0.002338
#> sex         -0.438453 0.079596   0.077022
#> tbf          0.270864 0.036662   0.033802
#>
#> 95% Confidence Intervals:
#>              Estimate       LCI       UCI LCI (btstr) UCI (btstr)
#> (Intercept)  0.473398  0.185743  0.761054    0.238365    0.747621
#> vat          0.207598  0.140549  0.274648    0.141959    0.282956
#> age          0.009478  0.004385  0.014570    0.004471    0.013680
#> sex         -0.438453 -0.594458 -0.282448   -0.584502   -0.284620
#> tbf          0.270864  0.199007  0.342721    0.201497    0.337719
#> Bootstrap Confidence Intervals are based on 999 bootstrap replicates using percentiles
#>
#> The measurement error is corrected for by application of regression calibration
#>
#> Coefficients Uncorrected Model:
#>               Estimate Std. Error  t value  Pr(>|t|)
#> (Intercept)  0.5097640  0.1264211   4.0323 6.185e-05
#> wc           0.0969705  0.0137957   7.0290 5.308e-12
#> age          0.0113271  0.0022048   5.1374 3.695e-07
#> sex         -0.7095274  0.0390086 -18.1890 < 2.2e-16
#> tbf          0.3878267  0.0201489  19.2481 < 2.2e-16
#>
#> 95% Confidence Intervals:
#>              Estimate       LCI       UCI
#> (Intercept)  0.509764  0.261517  0.758011
#> wc           0.096970  0.069881  0.124060
#> age          0.011327  0.006998  0.015657
#> sex         -0.709527 -0.786127 -0.632928
#> tbf          0.387827  0.348261  0.427392
#>
#> Residual standard error: 0.3123469 on 645 degrees of freedom

Two types of 95% confidence intervals are shown in the output of the summary() object. Bootstrap confidence intervals and Delta method confidence intervals. The default method to constructing confidence intervals in mecor is the Delta method. Further, Fieller method confidence intervals and zero variance method confidence intervals can be constructed with summary():

# fieller method ci and zero variance method ci and se's for 'rc_fit'
summary(rc_fit, zerovar = TRUE, fieller = TRUE)
#>
#> Call:
#> mecor(formula = ir_ln ~ MeasError(substitute = wc, reference = vat) +
#>     age + sex + tbf, data = vat, method = "standard", B = 999)
#>
#> Coefficients Corrected Model:
#>              Estimate       SE SE (btstr) SE (zerovar)
#> (Intercept)  0.473398 0.146766   0.128033     0.126665
#> vat          0.207598 0.034210   0.034857     0.029534
#> age          0.009478 0.002598   0.002338     0.002236
#> sex         -0.438453 0.079596   0.077022     0.069276
#> tbf          0.270864 0.036662   0.033802     0.031805
#>
#> 95% Confidence Intervals:
#>              Estimate       LCI       UCI LCI (btstr) UCI (btstr) LCI (zerovar)
#> (Intercept)  0.473398  0.185743  0.761054    0.238365    0.747621      0.225140
#> vat          0.207598  0.140549  0.274648    0.141959    0.282956      0.149712
#> age          0.009478  0.004385  0.014570    0.004471    0.013680      0.005096
#> sex         -0.438453 -0.594458 -0.282448   -0.584502   -0.284620     -0.574231
#> tbf          0.270864  0.199007  0.342721    0.201497    0.337719      0.208528
#>             UCI (zerovar) LCI (fieller) UCI (fieller)
#> (Intercept)      0.721657            NA            NA
#> vat              0.265484      0.145068      0.281464
#> age              0.013860            NA            NA
#> sex             -0.302675            NA            NA
#> tbf              0.333201            NA            NA
#> Bootstrap Confidence Intervals are based on 999 bootstrap replicates using percentiles
#>
#> The measurement error is corrected for by application of regression calibration
#>
#> Coefficients Uncorrected Model:
#>               Estimate Std. Error  t value  Pr(>|t|)
#> (Intercept)  0.5097640  0.1264211   4.0323 6.185e-05
#> wc           0.0969705  0.0137957   7.0290 5.308e-12
#> age          0.0113271  0.0022048   5.1374 3.695e-07
#> sex         -0.7095274  0.0390086 -18.1890 < 2.2e-16
#> tbf          0.3878267  0.0201489  19.2481 < 2.2e-16
#>
#> 95% Confidence Intervals:
#>              Estimate       LCI       UCI
#> (Intercept)  0.509764  0.261517  0.758011
#> wc           0.096970  0.069881  0.124060
#> age          0.011327  0.006998  0.015657
#> sex         -0.709527 -0.786127 -0.632928
#> tbf          0.387827  0.348261  0.427392
#>
#> Residual standard error: 0.3123469 on 645 degrees of freedom

Fieller method confidence intervals are only constructed for the corrected covariate (in this case $$X$$).

## Replicates study

The simulated data set bloodpressure in mecor is a replicates study. A replicates study includes a subset of individuals of whom the error-prone substitute exposure is repeatedly measured. The dataset bloodpressure contains 1000 observations of the outcome $$creatinine$$, three replicate measures of the error-prone exposure systolic blood pressure $$sbp30, sbp60$$ and $$sbp120$$, and one covariates age $$age$$. It is assumed that there is ‘random’ measurement error in the repeatedly measured substitute exposure measure.

# load replicates study
data("bloodpressure", package = "mecor")
#>   creatinine age    sbp30    sbp60    sbp90   sbp120
#> 1   53.75670  27 120.7987 113.2812 118.0705 124.2282
#> 2   63.08498  36 121.7254 106.8143 118.9882 115.1341
#> 3   60.04718  31 108.8798 119.6577 106.5588 117.5473
#> 4   62.42976  43 116.5566 117.4964 126.3625 121.7148
#> 5   61.31801  25 123.3018 116.4629 112.0310 109.8754
#> 6   50.60952  35 124.9119 129.0927 129.0224 114.0828

When ignoring the measurement error in $$sbp30$$, one would naively regress $$sbp30$$, $$age$$ on $$creatinine$$. Which results in a biased estimation of the exposure-outcome association:

# naive estimate of the exposure-outcome association
lm(creatinine ~ sbp30 + age,
data = bloodpressure)
#>
#> Call:
#> lm(formula = creatinine ~ sbp30 + age, data = bloodpressure)
#>
#> Coefficients:
#> (Intercept)        sbp30          age
#>     41.3050       0.1165       0.1651

Or alternatively, one could calculate the mean of each of the three replicate measures. Yet, this would still lead to a biased estimation of the exposure-outcome association:

## calculate the mean of the three replicate measures
bloodpressure$sbp_123 <- with(bloodpressure, rowMeans(cbind(sbp30, sbp60, sbp120))) # naive estimate of the exposure-outcome association version 2 lm(creatinine ~ sbp_123 + age, data = bloodpressure) #> #> Call: #> lm(formula = creatinine ~ sbp_123 + age, data = bloodpressure) #> #> Coefficients: #> (Intercept) sbp_123 age #> 35.4293 0.1641 0.1685 For an unbiased estimation of the exposure-outcome association, one could use regression calibration using mecor(): mecor(formula = creatinine ~ MeasError(sbp30, replicate = cbind(sbp60, sbp120)) + age, data = bloodpressure) #> #> Call: #> mecor(formula = creatinine ~ MeasError(sbp30, replicate = cbind(sbp60, #> sbp120)) + age, data = bloodpressure) #> #> Coefficients Corrected Model: #> (Intercept) cor_sbp30 age #> 32.6298873 0.1862331 0.1717354 #> #> Coefficients Uncorrected Model: #> (Intercept) sbp30 age #> 41.3050286 0.1165333 0.1650849 Instead of using the reference argument in the MeasError() object, the replicate argument is used. Standard errors of the regression calibration estimator and confidence intervals can be constructed similar to what was shown for an internal validation study. ## Calibration study The simulated data set sodium in mecor is a outcome calibration study. In a calibration study, two types of measurements are used to measure the outcome (or exposure). A measurement method prone to ‘systematic’ error, and a measurement method prone to ‘random’ error. The measurement prone to ‘systematic’ error is observed in the full study, the measurement prone to ‘classical’ error is observed in a subset of the study and repeatedly measured. The dataset sodium contains 1000 observations of the systematically error prone outcome $$recall$$, the randomly error prone outcome $$urinary1$$ and $$urinary2$$, and the exposure (in our case a indicator for diet) $$diet$$. The two replicate measures of the outcome prone to random error are observed in 498 individuals (approximately 50 percent). # load calibration study data("sodium", package = "mecor") head(sodium) #> recall diet urinary1 urinary2 #> 1 3.033925 1 3.249682 3.505636 #> 2 3.703586 0 4.416647 5.041728 #> 3 3.637268 1 NA NA #> 4 3.892225 0 5.125907 5.033366 #> 5 3.625387 1 3.362000 4.626138 #> 6 3.754797 0 NA NA When ignoring the measurement error in $$recall$$, one would naively regress $$diet$$ on $$recall$$. Which results in a biased estimation of the exposure-outcome association: ## uncorrected regression lm(recall ~ diet, data = sodium) #> #> Call: #> lm(formula = recall ~ diet, data = sodium) #> #> Coefficients: #> (Intercept) diet #> 3.8820 -0.3052 Alternatively, one could use the first half of the study population and use the mean of each of the two replicate measures. This would lead to an unbiased estimation of the exposure-outcome association since there is random measurement error int he replicate measures: ## calculate mean of three replicate measures sodium$urinary_12 <- with(sodium, rowMeans(cbind(urinary1, urinary2)))
## uncorrected regression version 2
lm(urinary_12 ~ diet,
data = sodium)
#>
#> Call:
#> lm(formula = urinary_12 ~ diet, data = sodium)
#>
#> Coefficients:
#> (Intercept)         diet
#>      4.5941      -0.5041

For an unbiased estimation of the exposure-outcome association, one could alternatively use standard regression calibration using mecor():

mecor(formula = MeasError(substitute = recall, replicate = cbind(urinary1, urinary2)) ~ diet,
data = sodium)
#>
#> Call:
#> mecor(formula = MeasError(substitute = recall, replicate = cbind(urinary1,
#>     urinary2)) ~ diet, data = sodium)
#>
#> Coefficients Corrected Model:
#> (Intercept)        diet
#>   4.6075011  -0.4843495
#>
#> Coefficients Uncorrected Model:
#> (Intercept)        diet
#>   3.8819732  -0.3051777

Standard errors of the regression calibration estimator and confidence intervals can be constructed similar to what was shown for an internal validation study.

## External validation study

The simulated data set heamoglogin_ext in mecor is a external outcome-validation study. An external validation study is used when in the main study, no information is available to correct for the measurement error in the outcome $$Y$$ (or exposure). Suppose for example that venous heamoglobin levels $$venous$$ are not observed in the internal outcome-validation study haemoglobin. An external validation study is a (small) sub study containing observations of the reference measure venous heamoglobin levels $$venous$$, the error-prone substitute measure $$capillary$$ (and the covariate(s) $$Z$$ in case of an covariate-validation study) of the original study. The external validation study is then used to estimate the calibration model, that is subsequently used to correct for the measurement error in the main study.

# load internal covariate validation study
data("haemoglobin_ext", package = "mecor")
#>   capillary   venous
#> 1  104.7269 115.3023
#> 2  133.9946 119.7616
#> 3  104.0304 108.0562
#> 4  119.0214 121.1780
#> 5  114.3891 111.7864
#> 6  111.7754 112.8943
data("haemoglobin", package = "mecor")

Suppose reference measure $$X$$ is not observed in dataset icvs. To correct the bias in the naive association between exposure $$X^*$$ and outcome $$Y$$ given $$Z$$, using the external validation study, one can proceed as follows using mecor():

# Estimate the calibration model in the external validation study
calmod <- lm(capillary ~ venous,
data = haemoglobin)
# Use the calibration model for measurement error correction:
mecor(MeasErrorExt(substitute = capillary, model = calmod) ~ supplement,
data = haemoglobin)
#>
#> Call:
#> mecor(formula = MeasErrorExt(substitute = capillary, model = calmod) ~
#>     supplement, data = haemoglobin)
#>
#> Coefficients Corrected Model:
#> (Intercept)  supplement
#>   117.99341     6.97392
#>
#> Coefficients Uncorrected Model:
#> (Intercept)  supplement
#>  124.452261    7.764702

In the above, a MeasErrorExt() object is used, indicating that external information is used for measurement error correction. The model argument of a MeasErrorExt() object takes a linear model of class lm (in the above calmod). Alternatively, a named list with the coefficients of the calibration model can be used as follows:

# Use coefficients for measurement error correction:
mecor(MeasErrorExt(capillary, model = list(coef = c(-7, 1.1))) ~ supplement,
data = haemoglobin)
#>
#> Call:
#> mecor(formula = MeasErrorExt(capillary, model = list(coef = c(-7,
#>     1.1))) ~ supplement, data = haemoglobin)
#>
#> Coefficients Corrected Model:
#> (Intercept)  supplement
#>   119.50206     7.05882
#>
#> Coefficients Uncorrected Model:
#> (Intercept)  supplement
#>  124.452261    7.764702