Is the pain worth it?: Can Rcpp speed up Passing Bablok Regression?

Background

R dogma is that for loops are bad because they are slow but this is not the case in C++. I had never programmed a line of C++ as of last week but my beloved firstborn started university last week and is enrolled in a C++ intro course, so I thought I would try to learn some and see if it would speed up Passing Bablok regression.

Passing Bablok Regression

As mentioned in the past, the field of Clinical Chemistry has a peculiar devotion to Passing Bablok regression… and hey, why not?

Here is the code for a minimal implementation of Passing Bablok regression as discussed in this paper. This is the scale-invariant version.

So let’s make some fake data and see what we get:

Just to sanity check, we can get the coefficients from the mcr() package.

Ok, looks good.

Rcpp

The Rcpp package permits compiling and execution of C++ code from within R. This can be good for computationally intensive tasks. Here is my child-like attempt at recapitulation of the R script above.

Saving this to a local directory as PB_Reg.cpp, we can compile it and call the function into the R session as follows:

And run it:

Looks good! But is it faster? Like really faster? Let’s find out. And let’s also compare it to what the compiler() package produces:

test replications elapsed relative user.self sys.self user.child sys.child
3 Rcpp 100 0.024 1.000 0.024 0.000 0 0
2 Compiler Package 100 0.214 8.917 0.214 0.000 0 0
1 Rscript 100 0.217 9.042 0.213 0.004 0 0

So this makes C++ code about 9x faster than R source code. Not bad but in this case it was probably not worth the effort. Oh well. I learned something. Incidentally, the compiler() package did not help much in this case as it is only marginally better than raw R source. I have seen better results from compiler() in other cases.

Final thought

Speaking of speed:

“Free yourself, like a gazelle from the hand of the hunter, like a bird from the snare of the fowler.”

Proverbs 6:5


A Shiny App for Passing Bablok and Deming Regression

Background

Back in 2011 I was not aware of any tool in R for Passing Bablok (PB) regression, a form of robust regression described in a series of three papers in Clinical Chemistry and Laboratory Medicine (then J Clin Chem and Biochem) available here, here and here. For reasons that are not entirely clear to me, this regression methodology is favoured by clinical chemists but seems largely ignored by other disciplines. However since reviewers clinical chemistry journals will demand the use of PB regression, it seemed expeditious to me to code it in R. This is what spawned a small project for a piece of software to do PB (and Deming and ordinary least squares) regression using a self-contained executable that could be downloaded, unzipped on a Windows Desktop and just ran. You can download here and instructions for installation and use are here and here respectively. The calculations are all done in R, the GUI is built with Python and Py-Qt4 and the executable with cx_freeze. I made it run without an installer because hospital IT often refuse to install software that has not been officially vetted and purchased. The tool was a lot more popular than I anticipated now having about 2000 downloads. In any case, maintenance, upgrades, bug fixing and dealing with operating system updates that break things (like OSX El Capitan's security policies) are no-fun so a Shiny based solution to the same problem makes a lot of sense.

Update

Since 2011, statisticians at Roche Diagnostics programmed the mcr package for PB and Deming regression. Additionally, there is also the MethComp package and the deming package from the Mayo Clinic which both offer PB regression.

Shiny App

Enter Burak Bahar, a like-minded Clinical Pathologist who is currently doing a fellowship at Yale. He liked my cp-R program but he saw the need for a web-based equivalent.

Burak and his wife Ayse, also a physician, have coded a Shiny App for doing Deming, PB and least squares regression in R which is capable of producing publication quality figures and provides all the regression statistics you would need for method-validation or publication. It can also produce a regression report in PDF, Word or HTML. The dynamic duo of the Bahar-MDs deserve all credit here as my only contribution related to suggestions related to usability. This project was presented at the 2016 American Association of Clinical Chemistry meeting in Philadelphia.

The app URL is bahar.shinyapps.io/method_compare. Go to the data tab on the left and then cut and paste your data from an spreadsheet program. Shortcuts CTRL-C (copy) and CTRL-V (paste) work natively in the table. The table is pre-populated with some random data for demonstration purposes. Once your data is pasted in, click on the Plots tab and choose the Bland-Altman or Scatter Plot.

Example

Here is an image generated with the Bahar Shiny app using method comparison data obtained from St. Paul's Hospital Laboratory in migrating from Siemens Immulite 2000 XPi to Roche Cobas e601 for Calcitonin determination. Don't worry, we did more than 33 comparison–I am just showing the low end.

regression

BA

Try adjusting some of the plot parameters. The figures will update in real time. Thanks to Burak and Ayse Bahar for your work!

(Dan's) Parting Thought

There are straight lines that matter a lot more than regression.

I will make justice the measuring line and righteousness the plumb line
(Isa 28:17)

Deming and Passing Bablok Regression in R

Regression Methods

In this post we will be discussing how to perform Passing Bablok and Deming regression in R. Those who work in Clinical Chemistry know that these two approaches are required by the journals in the field. The idiosyncratic affection for these two forms of regression appears to be historical but this is something unlikely to change in my lifetime–hence the need to cover it here.

Along the way, we shall touch on the ways in which Deming and Passing Bablok differ from ordinary least squares (OLS) and from one another.

Creating some random data

Let's start by making some heteroscedastic random data that we can use for regression. We will use the command set.seed() to begin with because by this means, the reader can generate the same random data as the post. This function takes any number you wish as its argument, but if you set the same seed, you will get the same random numbers. We will generate 100 random \(x\) values in the uniform distribution and then an accompanying 100 random \(y\) values with proportional bias, constant bias and random noise that increases with \(x\). I have added a bit of non–linearity because we do see this a fair bit in our work.

The constants I chose are arbitrary. I chose them to produce something resembling a comparison of, say, two automated immunoassays.

Let's quickly produce a scatter plot to see what our data looks like:

plot of chunk unnamed-chunk-2

Residuals in OLS

OLS regression minimizes the sum of squared residuals. In the case of OLS, the residual of a point is defined as the vertical distance from that point to the regression line. The regression line is chosen so that the sum of the squares of the residuals in minimal.

OLS regression assumes that there is no error in the \(x\)–axis values and that there is no heteroscedasticity, that is, the scatter of \(y\) is constant. Neither of these assumptions is true in the case of bioanaytical method comparisons. In contrast, for calibration curves in mass–spectrometry, a linear response is plotted as a function of pre–defined calibrator concentration. This means that the \(x\)–axis has very little error and so OLS regression is an appropriate choice (though I doubt that the assumption about homoscedasticity is generally met).

OLS is part of R's base package. We can find the OLS regression line using lm() and we will store the results in the variable lin.reg.

plot of chunk unnamed-chunk-3

Just to demonstrate the point about residuals graphically, the following shows them in vertical red lines.

plot of chunk unnamed-chunk-4

Deming Regression

Deming regression differs from OLS regression in that it does not make the assumption that the \(x\) values are free of error. It (more or less) defines the residual as the perpendicular distance from a point to its fitted value on the regression line.

Deming regression does not come as part of R's base package but can be performed using the MethComp and mcr packages. In this case, we will use the latter. If not already installed, you must install the mcr package with install.packages("mcr").

Then to perform Deming regression, we will load the mcr library and execute the following using the mcreg() command, storing the output in the variable dem.reg.

By performing the str() command on dem.reg, we can see that the regression parameters are stored in the slot @para. Because the authors have used an S4 object as the output of their function, we don't address output as we would in lists (with a $), but rather with an @.

The intercept and slope are stored in demreg@para[1] and dem.reg@para[2] respectively. Therefore, we can add the regression line as follows:

plot of chunk unnamed-chunk-7

To emphasize how the residuals are different from OLS we can plot them as before:

plot of chunk unnamed-chunk-8

We present the figure above for instructional purposes only. The usual way to present a residuals plot is to show the same picture rotated until the line is horizontal–this is a slight simplification but is essentially what is happening:

plot of chunk unnamed-chunk-9

Ratio of Variances

It is important to mention that if one knows that the \(x\)–axis method is subject to a different amount of random analytical variability than the \(y\)–axis method, one should provide the ratio of the variances of the two methods to mcreg(). In general, this requires us to have “CV” data from precision studies already available. Another approach is to perform every analysis in duplicate by both methods and use the data to estimate this ratio.

If the methods happen to have similar CVs throughout the analytical range, the default value of 1 is assumed. But suppose that the ratio of the CVs of the \(x\) axis method to the \(y\)–axis method was 1.2, we could provide this in the regression call by setting the error.ratio parameter. The resulting regression parameters will be slightly different.

Weighting

In the case of heteroscedastic data, it would be customary to weight the regression which in the case of the mcr package is weighted as \(1/x^2\). This means that having 0's in your \(x\)–data will cause the calculation to “crump”. In any case, if we wanted weighted regression parameters we would make the call:

And plotting both on the same figure:

plot of chunk unnamed-chunk-12

Passing Bablok

Passing Bablok regression is not performed by the minimization of residuals. Rather, all possible pairs of \(x\)–\(y\) points are determined and slopes are calculated using each pair of points. Work–arounds are undertaken for pairs of points that generate infinite slopes and other peculiarities. In any case, the median of the \(\frac{N(N-1)}{2!}\) possible slopes becomes the final slope estimate and the corresponding intercept can be calculated. With regards to weighted Passing Bablok regression, I’d like to acknowledge commenter glen_b for bringing to my attention that there is a paradigm for calculating the weighted median of pairwise slopes. See the comment section for a discussion.

Passing Bablok regression takes a lot of computational time as the number of points grows, so expect some delays on data sets larger than \(N=100\) if you are using an ordinary computer. To get the Passing Bablok regression equation, we just change the method.reg parameter:

and the procedures to plot this regression are identical. The mcreg() function does have an option for Passing Bablok regression on large data sets. See the instructions by typing help("mcreg") in the R terminal.

Outlier Effects

As a consequence of the means by which the slope is determined, the Passing Bablok method is relatively resistant to the effect of outlier(s) as compared to OLS and Deming. To demonstrate this, we can add on outlier to some data scattered about the line \(y=x\) and show how all three methods are affected.

plot of chunk unnamed-chunk-15

Because of this outlier, the OLS slope drops to 0.84, the Deming slope to 0.91, while the Passing Bablok is much better off at 0.99.

Generating a Pretty Plot

The code authors of the mcr package have created a feature such that if you put the regression model inside the plot function, you can quickly generate a figure for yourself that has all the required information on it. For example,

plot of chunk unnamed-chunk-16

But this method of out–of–the–box figure is not very customizable and you may want it to appear differently for your publication. Never fear. There is a solution. The MCResult.plot() function offers complete customization of the figure so that you can show it exactly as you wish for your publication.

custom mcr plot

In this example, I have created semi–transparent “darkorchid4” (hex = #68228B) points and a semi–transparent blue (hex = #0000FF) confidence band of the regression. Maybe darkorchid would not be my first choice for a publication after all, but it demonstrates the customization. Additionally, I have suppressed my least favourite features of the default plot method. Specifically, the sub="" term removes the sentence at the bottom margin and the add.grid = FALSE prevents the grid from being plotted. Enter help(MCResult.plot) for the complete low–down on customization.

Conclusion

We have seen how to perform Deming and Passing Bablok regression in the R programming language and have touched on how the methods differ “under the hood”. We have used the mcr to perform the regressions and have shown how you can beautify your plot.

The reader should have a look at the rlm() function in the MASS package and the rq() function in the quantreg package to see other robust (outlier–resistant) regression approaches. A good tutorial can be found here

I hope that makes it easy for you.

-Dan

May all your paths (and regressions) be straight:

Trust in the Lord with all your heart
and lean not on your own understanding;
in all your ways submit to him,
and he will make your paths straight.

Proverbs 3:5-6