Dr Lubin's reply concerning ecologic LNT study

[FIELDRW@aol.com]

Hopefully, with Melissa's advice, it will print out this time.  Thanks again 
for your patience.  Bill Field

Dr. Lubin's reply concerning Dr Cohen's ecologic LNT study.

 I feel that I must comment on the exchange by Cohen and Klugh.  Dr. Cohen's 
suggestion that because I made no attempt to claim his reward, I must have 
accepted the adequacy of his responses to articles by me and others is  
ludicrous.  It is not that I don't believe Cohen's results, but that his 
results are not relevant for determining risk to individuals.  Upon 
re-reading his responses to the exchange in Health Physics and on this 
listserve, I can only conclude that Dr. Cohen has entirely missed the point 
of my comments.  Let's try one more time.
 
 1.  It is clear that Cohen's ecological analysis is markedly discrepant from 
the analytic studies of residential radon exposure and of radon-exposed 
miners, from animal studies and from current dosimetric/biophysical models.  
As I made
clear in my last letter in Health Physics, Cohen's linear-quadric model for 
lung cancer mortality rates and residential radon is not supported by the 
case-control studies or the miner studies.  His model in fact predicts a 
strong protective effect of living in houses with concentrations under about 
300 Bq/m3 - this pattern just does not occur in the analytic data.   
 
 The relevant question then becomes -- how are we to interpret Cohen's 
results in light of the findings from the analytic studies?  More 
importantly, when considering whether and to what extent residential radon 
increases (or in
 light of Cohen's result, decreases) the risk of lung cancer, is it even 
necessary that Cohen's results should be "explained"?  The main point of my 
articles, as well as articles by Greenland and Robins, Samet et al, 
Piantadosi, Muirhead et al, and others, is that the answer is an emphatic no 
to the latter question. These articles show that the methodology of 
ecological analysis itself has such limitations that no meaningful inference 
from the relationship observed at the grouped level can be made to the 
dose-response relationship for individuals. Thus, Cohen's regression results 
cannot serve as an evaluator of radon effects for individuals.  This is why 
epidemiologists use ecological analyses only for  hypothesis generating and 
not hypothesis testing.  In the real world of epidemiology, in order to have 
any credence, an association observed at the ecological level must first be 
demonstrated using individual-level studies. The converse is never the case.  
One would never consider that results from analytic studies needed to be 
"validated" by ecological analysis.  Thus, there is little point in trying to 
identify any specific reason why Cohen's regression results in a negative 
trend.  The methodology is intrinsically flawed.  Given diverse results from 
ecological analyses and from analytic studies, analytic studies a priori have 
the greater claim to validity.
 
What is the flaw in ecological studies?  Again, many articles have 
demonstrated that the principal source of the problem is that correlations 
among risk factors can occur within counties.  Moreover, the correlations of 
the risk factors may vary among the counties.  Therefore, one cannot simply 
define a model for the within county correlations and apply it across 
counties and claim adjustment of these effects.  This is the central 
rationale for the proposal by Shpard and Prentice to "correct" ecological 
studies by randomly sampling populations within county in order to estimate 
the joint distribution of risk factors.  Cohen's repeated assertions that the 
"ecological fallacy" does not apply, does not make it so.  He cannot create 
models that account for both the risk factor correlations within county and 
their variations across counties.  My original paper in Health Physics shows 
that the amount of correlation between radon level and another risk factor 
can be small indeed, on the order of 0.05.
 
 2.  Cohen suggests that his analysis is not confounded because the negative 
trend of lung cancer rates and county "mean" radon level is unchanged after 
adjusting for hundreds of different factors.  That is not the point at all, 
and indeed is irrelevant to the control of within county confounding.  One 
can never adjust for factors that operate within county by endlessly adding 
more and more county-level information.  His ecological analysis has no more 
claim to validity if he were to add thousands of additional county-level 
variables. County-level factors are not the source of the limitations.
 
 3.  While the confounding problem is really paramount, it is also the case 
that data used in many ecological analyses are often of limited quality and 
difficult to interpret.  Cohen's data are no exception.  Lung cancer 
mortality from death certificates are often misspecified and covariate 
information is of poor quality.  Of particular concern, Cohen uses mortality 
rates where the disease-relevant exposure period is at least a decade or more 
prior to available radon data.  The county "average" radon concentration may 
bear little relationship to the "average" county radon concentration 
prevailing 5-30 years prior to the mortality data.  The population 
composition, risk factors, as well as lung cancer mortality rates, have 
changed considerably in recent decades. (See for example the NCI cancer atlas 
for changes in lung cancer mortality, ). This problem is exacerbated by the 
further limitation that average radon level (and other risk factors) for a 
county does not translate into lung cancer-relevant dose, and that the 
correlations among risk factors may vary over time.
 
Residential radon studies in general do not suffer from the flaw that radon 
measurements post­date the disease occurrence by 10-30 years.  While radon 
measurements are contemporary, in residential studies, interviews provide 
detailed information on residential history, so investigators know precisely 
how long subjects were resident in the various houses, and on house 
modifications, heating systems, etc.  In the Iowa study, enrollment in the 
study required that
 the subject has lived in the current house for at least the preceding 20 
years.
 
 4.  It must also be pointed out that not all ecological studies agree with 
Cohen's results, and big does not equate with valid.  Many ecological studies 
have been published; some show decreasing trend, no trend, or increasing 
trend.
In an attempt to circumvent the limitation of mortality data and poor 
exposure data, several investigators have used population registry files on 
lung cancer cases to create lung cancer incidence rates for counties.  
Analyzing these incidence rates together with county radon measurements and 
other information from population-based case-control studies, investigators 
have found patterns of associations that show increasing risks with radon.  
None show decreasing
risks.
 
 This exchange has been going on for nearly a decade.  To paraphrase 
Piantadosi, given results from analytic studies and ecological studies, the 
former must carry the greater weight in our considerations.  Thus, it is time 
to move
 on and address the many important questions that remain: what are the 
consequences of exposure measurement error on risk estimates; what is a 
realistic level of uncertainty on the risk associated with long-term 
residence in houses in the
 range of 75-200 Bq/m3; are there specific genetic polymorphisms that define 
susceptible sub-populations?
 
 Jay Lubin 
 
 Jay Lubin, PhD
 National Cancer Institute
 Biostatistics Branch, EPS/8042
 6120 Executive Blvd
 Bethesda, MD 20892-7244
 Tel: 301-496-3357
 Fax: 301-402-0081
 Email: lubinj@exchange.nih.gov <mailto:lubinj@exchange.nih.gov>  >>
--------------------------------------
Bill Field
mailto:bill-field@uiowa.edu
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