The ratio-nal approach to predicted TLC

I’ve been reading Miller et al’s Laboratory evaluation of Pulmonary Function which was published in 1987. That was an interesting time since PFT equipment manufacturers had mostly transitioned to computerized systems but there were still a lot of manual systems in the field. For this reason the book’s instructions are still oriented mostly around manual pulmonary function testing and there are numerous warnings about double-checking the results from automated systems.

The book includes extensive discussion on the calculations and formulas used for testing which makes it useful as a teaching resource. The authors were also very concerned about the correct way to run a PFT lab so there is a fair amount of discussion about staff requirements for education and training (including the medical director) and staff behavior and conduct. To this end each chapter includes extensive instructions on the proper way to perform tests and treat patients. Although the tone of this is somewhat dated and I’d like to say these kind of reminders shouldn’t be necessary, it doesn’t hurt to set a standard on the level of professionalism we should aspire to.

What caught my eye though, was a section in the chapter on Normal Values titled Interdependence of Normal Values which discussed of the value of deriving predicted TLC from predicted FVC. The authors were concerned that reference equations for different tests (and not just lung volumes) were being selected without concern for how well they fit together. I’ve previously written about the problems that results when inserting the reference equation for FVC into the reference equations for lung volumes. In one instance, the TLC was adjusted so that the final predicted TLC was equal to RV + VC, but this meant that TLC (and IC) were changed from the original reference equations. In another, the FVC was just substituted for SVC without adjustment which meant that RV + VC was not equal to TLC and IC + ERV was not equal to VC and this makes interpreting results problematic. What this means however, is that almost 30 years after this was published, this problem is still around.

As a solution, the authors point out that ratios, such as the FEV1/FVC ratio and the RV/TLC ratio tend to be relatively independent of height.

Since:

TLC = FVC + RV

This can be mathematically re-written as:

Which means that TLC can be derived from predicted FVC if the RV/TLC ratio is known.

So how accurate is the TLC derived this way? The first problem is that even in 1987 there were a variety of RV/TLC ratio reference equations.

RV_TLC_Ratio_Male_Ht_Independent RV_TLC_Ratio_Female_Ht_Independent

Interestingly, males and females have slightly different patterns when their predicted RV/TLC ratios are compared. Males tend to have lower RV/TLC ratios overall; show the largest differences between predicted RV/TLC ratios at age 20, and these differences decrease with increasing age. Females tend to have higher RV/TLC ratios overall; show the smallest differences between predicted RV/TLC ratios at age 20, and these differences increase with increasing age.

At the time the book was written age was the only variable in all of the RV/TLC reference equations but since 1987 at least two lung volume studies have been published that do not have reference equation specifically for the RV/TLC ratio. Instead it was calculated from the reference equations for RV and TLC and these included height in one way or another as a variable. Although the differences are less dramatic for females than for males, both studies show that the RV/TLC ratio actually decreases with increasing height.

RV_TLC_Ratio_Male_Ht_Dependent

RV_TLC_Ratio_Female_Ht_Dependent

This indicates that the RV/TLC ratio may not be completely independent of height, but the differences are relatively small, and in fact are within the range of the RV/TLC ratios calculated from the reference equations that only had age as a variable.

How well does the TLC derived from predicted FVC compare to TLC calculated from the standard reference equations?

For males the majority of TLC reference equations height is the only variable and single equation that does include age (Crapo) shows an increasing (?!) TLC with age. When two of the more common FVC reference equations (NHANESIII and Morris) are used to derive TLC this resulted in patterns that were quite different from the standard TLC reference equations. For the NHANESIII FVC, the TLC had a curvilinear pattern which increased to a maximum at about age 40, and decreased thereafter. For the Morris FVC, TLC decreased fairly constantly with age. This alone must show that the FVC derived TLC is incorrect, doesn’t it?

Not necessarily. One study of lung volumes with a study group aged 65 to 85 showed a declining TLC with increasing age and the results from that reference equation is actually similar to the NHANESIII TLC over the same age range.

TLC_Male

For females, about half of the standard TLC reference equations include age as a factor and about half don’t. For those that do include age TLC decreases with increasing age and the Morris TLC showed a similar decline. The NHANESIII TLC however, showed a marked curvilinear pattern that peaked at about age 50. The TLC from the 65-85 study group had approximately the same slope as the NHANESIII over the same age range but was lower.

TLC_Female

When I started looking at this I expected that the FVC-derived TLC values would probably be similar to the standard TLC reference equations but it’s actually a bit of a mess, isn’t it?.

Here’s the problem though: the formula used by Miller et al to derive TLC is absolutely correct, particularly since it’s merely a mathematical restatement of TLC = FVC + RV. So why does it appear to fail? Partly because of the assumption that one RV/TLC ratio applies to all populations but also because of differences between study populations and different statistical analyses. Most particularly it fails because the decline in FVC and increase in RV/TLC ratio that occur with age have different slopes.

What this does is to throw a spotlight on the problem of mixing-and-matching different lung volume and spirometry reference equations. All of the lung volume subdivisions (and ratios) have to add up correctly and there is no way to insert a predicted FVC without the need to alter multiple values. No matter how this is done the choice of which values to alter and how to alter them is a completely arbitrary decision.

Note: I understand the temptation to replace the SVC reference equation with an FVC reference equation. It is a common perception that because the study populations for FVC studies are usually be larger and the quality of the statistical analysis tends to be better that this makes the FVC reference equations “better” than the SVC reference equations. Another reason is so that the reported predicted VC for spirometry and lung volumes match because its “obvious” that they should be the same. The problem is that there is no easy and reliable way to insert a predicted FVC into predicted lung volumes without distorting one or the other.

When the reference equations for spirometry and lung volumes come from the same study population (notably Gutierriez et al), the FVC-derived TLC matches the reference equation TLC for all ages, genders and heights. Unfortunately using a single study population is not a guarantee, since choices made when performing statistical analysis on different elements (Marsh et al) can cause the FVC-derived TLC to differ from the same study’s reference equation TLC.

I think that Miller et al’s original point about ratios being relatively independent of height actually has a fair amount of merit. When compared to the FVC and TLC volumes that occur across the range human heights the differences in the FEV1/FVC ratio and RV/TLC ratio are miniscule. This probably means that we should be placing more emphasis on ratios in general (IC/ERV? FEV3/FVC?) when interpreting test results.

An interesting question that the FVC-derived TLC raises is whether the fact that TLC changes little with age (mostly for males, partly for females) is actually correct. All FVC-derived TLCs decrease with increasing age (at least above age 50 they do). As noted, this may be a function of the different age slopes for FVC and RV/TLC, but if so why does this difference exist?

Finally, there are surprisingly few lung volume reference equations for non-Caucasian populations (and shame on all of us for that) but those that exist have RV/TLC ratios that are essentially the same as Caucasians. This at least suggests that the RV/TLC is well preserved across all ethnicities. Many ethnicities that do not have lung volume reference equations do have spirometry reference equations. In these populations the standard practice is to estimate predicted TLC by subtracting a specific percentage from a Caucasian reference equation TLC. Wherever this percentage is questionable it could be verified to some degree by deriving TLC from the predicted FVC and an average RV/TLC ratio.

Technical note: The average of the height-independent RV/TLC ratio reference equations for males is:

RV/TLC ratio = (Age x 0.29125) + 14.7

For females, it is:

RV/TLC ratio = (Age x 0.3424) + 16.4

References:

[A] Cordero PJ, Morales P, Benlloch E, Miravet L, Cebrian J. Static Lung Volume: Reference values from a Latin population of Spanish descent. Respiration 1999; 66: 242-250.

[B] Crapo RO, Morris AH, Clayton PD, Nixon CR. Lung volume in healthy nonsmoking adults. Bull Eur Physiopathol Respir 1983; 18: 419-425

[C] Garcia-Rio F, Dorgham A, Pino JM, Villasante C, Garcia-Quero C, Alvarez-Sala R. Lung volume reference values for women and Men 65-85 years of age. Am J Respir Crit Care Med 2009; 180: 1083-1091.

[D] Gutierrez C, et al. Reference values of pulmonary function tests for Canadian caucasians. Can Respir J 2004; 6: 414-424.

[E] Hankinson JL, Odencrantz JR, Fedan, KB. Spirometric reference values from a sample of the general U.S. Population. Amer J Resp Crit Care 1999; 159: 179-187

[F] Marsh S, Aldington S, Williams M, Weatherall M, Shirtcliffe P, McNaughton A, Pritchard A, Beaseley R. Complete reference ranges for pulmonary function tests from a single New Zealand population. New Zealand Med J 2006; 119: N1244.

[G] Miller WF, Scacci R, Gast LR. Laboratory evaluation of Pulmonary Function. J.B. Lippincott Co, 1987.

[H] Morris JF, Koski A, Johnson LC. Spirometric standards for healthy nonsmoking adults. Am Rev Resp Dis 1971; 103: 57-67.

[I] Neder JA, Andreoni S, Castelo-Filho A, Nery LE. Reference values for lung function tests. I. Static Volume. Braz J Med Biol Res 1999; 32: 703-717

[J] Roberts CM, MacRae KD, Winning AJ, Adams L, Seed WA. Reference values and prediction equations for normal lung function in a non-smoking white urban population. Thorax 1991; 46: 643-650.

[K] Stocks J, Quanjer PH. Reference values for residual volume, function residual capacity and total lung capacity. Eur Respir J 1995; 8: 492-506.

Creative Commons License
PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.