Sjart st0162
Sjart st0162
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The Stata Journal (2009)
9, Number 2, pp. 175–196
     Abstract. The risk ratio can be a useful statistic for summarizing the results of
     cross-sectional, cohort, and randomized trial studies. I discuss several methods for
     estimating adjusted risk ratios and show how they can be executed in Stata, in-
     cluding 1) Mantel–Haenszel and inverse-variance stratified methods; 2) generalized
     linear regression with a log link and binomial distribution; 3) generalized linear
     regression with a log link, normal distribution, and robust variance estimator; 4)
     Poisson regression with a robust variance estimator; 5) Cox proportional hazards
     regression with a robust variance estimator; 6) standardized risk ratios from logis-
     tic, probit, complementary log-log, and log-log regression; and 7) a substitution
     method. Advantages and drawbacks are noted for some methods.
     Keywords: st0162, risk ratio, odds ratio
1    Introduction
The case–control study design is typically (but not always) used when outcomes are
rare in the population from which study subjects are sampled. In 1951, Cornfield noted
that when outcomes are sufficiently rare, the odds ratio from a case–control study will
approximate the population risk ratio for the association of an exposure with a disease
outcome. It was later realized that if controls are sampled as each case arises in time,
the odds ratio will estimate the incidence-rate ratio even when outcomes are common
(Greenland and Thomas 1982; Rodrigues and Kirkwood 1990; Rothman, Greenland,
and Lash 2008, 113–114). In Stata, case–control data can be analyzed using Mantel–
Haenszel stratified methods (cc, tabodds, mhodds), logistic regression (logistic), or
conditional logistic regression (clogit) to estimate adjusted odds ratios that usually
can be interpreted either as risk ratios (when outcomes are rare) or incidence-rate ratios
(when incidence density sampling is used).
    Cross-sectional, cohort, and randomized controlled trial designs with binary out-
comes can often be summarized by estimating odds ratios or risk ratios. If the study
outcome is sufficiently rare among exposed and unexposed study subjects, the odds
ratio for the exposure–outcome association will closely approximate the risk ratio. But
if the outcome is common and the risk ratio is not close to 1, the odds ratio will be
further from 1 compared with the risk ratio. Even if the outcome is rare in the entire
sample, if an adjustment is made for other variables, then the adjusted odds ratio will
c 2009 StataCorp LP                                                                     st0162
176                                   Methods for estimating adjusted risk ratios
be further from 1 than the adjusted risk ratio if the outcome is common in adjustment
variable subgroups that contribute a noteworthy portion of the outcomes (Greenland
1987).
    When summary odds and risk ratios differ, there is debate regarding which is prefer-
able. Some have argued that odds ratios are preferred because they are symmetric with
regard to the outcome definition (Walter 1998; Olkin 1998; Senn 1999; Newman 2001,
35–40; Cook 2002). Furthermore, when outcomes are common, a constant (homoge-
neous) adjusted odds ratio for all subjects may be more plausible than a constant risk
ratio (Levin 1991; Senn 1998; Cook 2002).
    Some who favor risk ratios feel they are more easily understood by physicians
(Sackett, Deeks, and Altman 1996). Others have noted that risk ratios have a desir-
able feature called collapsibility; in the absence of confounding, a weighted average of
stratum-specific risk ratios will equal the ratio from one 2 × 2 table of the pooled (col-
lapsed) counts from the stratum-specific tables (Miettinen and Cook 1981; Greenland
1987, 1991b; Greenland, Robins, and Pearl 1999; Newman 2001, 52–55; Rothman,
Greenland, and Lash 2008, 62). This means that a crude (unadjusted) risk ratio will not
change if we adjust for a variable that is not a confounder. In the absence of confound-
ing, the risk ratio estimates the change in risk, on a ratio scale, for the entire exposed
group due to exposure. Because of collapsibility, this risk ratio has a useful interpre-
tation as the ratio change in the average risk in the exposed group due to exposure.
It is not the average ratio change in risk (i.e., the average risk ratio) among exposed
individuals, except in the unlikely event that the risk ratios for all individuals are the
same (Greenland 1987).
    Odds ratios lack the property of collapsibility and therefore the interpretation of an
odds ratio is more limited; in the absence of confounding, it estimates the change in odds,
on a ratio scale, in the exposed group due to exposure. But it does not estimate either
the change in the average odds of the exposed due to exposure or the average change in
odds (i.e., the average odds ratio) among exposed individuals, not even if all individuals
had the same change in odds when exposed (Greenland 1987). The odds ratio will
estimate the average change in odds for exposed individuals only if all individual odds
ratios are the same and all individual risks without exposure are the same. Except in this
unlikely situation, the crude odds ratio will be closer to 1 than the average of stratum-
specific or individual odds ratios. Even in the absence of confounding, the adjusted
(conditional) odds ratio will be further from 1 than the crude (unadjusted or marginal)
odds ratio (Gail et al. 1984; Greenland 1987; Hauck et al. 1998; Steyerberg et al. 2000;
Newman 2001, 52–55; Rothman, Greenland, and Lash 2008, 62; Cummings 2009).
    For analysts who wish to estimate odds ratios for the association of exposure with
disease in a cross-sectional study, cohort study, or randomized trial, the statistical meth-
ods in Stata’s cc, tabodds, mhodds, and logistic commands can be used. If the goal is
to estimate risk ratios, these same methods can be used if outcomes are sufficiently rare
that odds ratios will closely approximate risk ratios. But if risk ratios are desired when
outcomes are common, odds ratio estimates will not suffice. In this article, I describe
methods for estimating adjusted risk ratios with confidence intervals (CIs) in Stata.
P. Cummings                                                                              177
Table 1. Deaths, total subjects, and risk of death for 192 women with breast cancer
followed for 5 years, by stage at diagnosis (I, II, III) and estrogen-receptor–level category
(low, high). Also, risk ratios within each cancer stage for death among women with low
versus high receptor levels.
     Receptor levels    Stage    Died    Total    Risk   Risk ratio for death
                                                         comparing women with low
                                                         versus high receptor levels
     Low                I        2       12       0.17   1.8
     High               I        5       55       0.09   1.0 (reference group)
     Low                II       9       22       0.41   1.8
     High               II       17      74       0.23   1.0 (reference group)
     Low                III      12      14       0.86   1.4
     High               III      9       15       0.60   1.0 (reference group)
      . use brcadat
      (Breast cancer data)
      . cs died low, by(stage) pool
          Cancer stage         RR         [95% Conf. Interval]      M-H Weight
I invoked the pool option so that the output shows both the Mantel–Haenszel combined
risk ratio and the pooled risk ratio obtained using inverse-variance weights. These
methods require that variables be treated as categorical, not continuous.
                                        OIM
              died    Risk Ratio     Std. Err.          z   P>|z|       [95% Conf. Interval]
   Above Stata reported that for iteration 0, the likelihood region was not concave.
When the command is run without the difficult option, Stata 10.0 will repeatedly
report a not-concave region and fail to converge. The difficult option changed Stata’s
convergence algorithm and solved the problem in this example, but that option may
not always work. The convergence problem arose because among women with Stage III
cancer and low estrogen-receptor levels, the risk of death was close to 1: 12/14 = 0.86.
When the risk is close to 1 in a stratum of the data, maximum-likelihood convergence
may fail. This problem has been discussed in several articles (Carter, Lipsitz, and Tilley
2005; Blizzard and Hosmer 2006; Lumley, Kronmal, and Ma 2006; Localio, Margolis,
and Berlin 2007).
    Wacholder (1986; Lumley, Kronmal, and Ma 2006) described a method that modi-
fied the convergence by truncating estimated risks to values slightly greater than 0 and
less than 1. This is implemented in Stata’s binreg command:
                                     EIM
              died   Risk Ratio   Std. Err.        z    P>|z|     [95% Conf. Interval]
                                        OIM
              died    Risk Ratio     Std. Err.     z    P>|z|    [95% Conf. Interval]
                                     Robust
              died         exp(b)   Std. Err.     z    P>|z|   [95% Conf. Interval]
   If the deaths were from a Poisson distribution, women would have nonnegative in-
teger counts of 0, 1, 2, 3, . . . , or more deaths. The data cannot be Poisson, because
no woman dies more than once. The data are from a binomial distribution, and the
binomial variance is assumed to be the proportion that died multiplied by 1 minus that
proportion. The standard error of the mean proportion is the square root of the variance
divided by the square root of the number of women, which is 0.0324477. This is the
standard error reported by ci, binomial:
     . ci died, binomial
                                                                        Binomial Exact
         Variable               Obs        Mean    Std. Err.         [95% Conf. Interval]
   If we use Poisson methods for these binomial data, the standard error for the outcome
proportion (risk) is too large: 0.03827 instead of 0.03245. As the outcome becomes less
common, the Poisson standard error will converge toward the binomial standard error
(Armitage, Berry, and Matthews 2002, 71–76). But in the breast cancer data, use of
Poisson regression to estimate risk ratios will produce standard errors, p-values, and CIs
that are too large:
    Above, the 95% CI for the low variable is wide, 0.93 to 2.86, compared with the CIs
from other methods. We can obtain standard errors and CIs that are approximately
correct by using a robust variance estimator, which can relax the assumption that the
data are from a Poisson distribution (Wooldridge 2002, 650–651; Greenland 2004a; Zou
2004; Carter, Lipsitz, and Tilley 2005). The robust variance estimator is sometimes
called the Huber, White, Huber–White, sandwich, or survey estimator, as well as other
names (Hardin and Hilbe 2007, 35–36). In Stata, we can invoke this estimator with the
vce(robust) option and the CI for the low variable becomes narrower, 1.07 to 2.48:
                                      Robust
              died             IRR   Std. Err.     z    P>|z|     [95% Conf. Interval]
                                    Robust
               _t   Haz. Ratio     Std. Err.     z    P>|z|    [95% Conf. Interval]
    The results above reproduce exactly the results from Poisson regression with the
robust variance estimator; the Poisson and Cox methods are identical when implemented
in this way. Options other than the Breslow method for dealing with tied survival times
will produce risk-ratio estimates for exposure to a low estrogen-receptor–level tumor
that are too large: 1) the efron option produces a risk ratio of 1.91, 2) the exactm
option yields 2.04, and 3) the exactp option risk ratio is 2.49.
      . #delimit ;
      delimiter now ;
      . predictnl lnrr =
      >   ln(
      >   sum(1/
      >   (1+exp(-(_b[_cons]+_b[stage2]*stage2+_b[stage3]*stage3+_b[low]))))
      >   /
      >   sum(1/
      >   (1+exp(-(_b[_cons]+_b[stage2]*stage2+_b[stage3]*stage3)))))
      >   , se(lnrr_se);
      . #delimit cr
      delimiter now cr
      . scalar rr = exp(lnrr[_N])
      . scalar upper = exp(lnrr[_N] + invnormal(1-.05/2)*lnrr_se[_N])
      . scalar lower = exp(lnrr[_N] - invnormal(1-.05/2)*lnrr_se[_N])
      . display "Risk ratio = " rr " 95% CI = " lower ", " upper
      Risk ratio = 1.6755988 95% CI = 1.0935713, 2.5673969
   The adjusted odds ratio for death among women with a low estrogen-receptor level–
tumor, compared with women with a high estrogen-receptor–level tumor, was 2.5. Be-
cause the outcome of death was common, this odds ratio does not closely approximate
the risk ratio.
    Above I used predictnl to estimate the ln of the risk ratio (lnrr variable); this
command can estimate nonlinear comparisons from regression coefficients. The se op-
tion estimated the standard error for the ln risk ratio using the delta method. To make
the output less cluttered, I used delimit to change how Stata recognizes the end of
a command line. To estimate the risk or probability of death, I used the expression
1/{1 + exp(−linear predictor)}. The first sum used by predictnl is for risk estimates
if all women had a low estrogen-receptor–level tumor, because the ln odds term for low
receptor status, b[low], is included in the sum, regardless of each woman’s actual recep-
tor status. In this first sum, the regression coefficients (which are ln odds estimates) for
 Istage 2 and Istage 3 were both multiplied by each woman’s observed cancer stage,
thereby standardizing the estimate to the observed distribution of cancer stage. Stata’s
sum() function is the running sum from the first record to the last, so the sum in the
last record of the data is the sum of all the estimated risks if all 192 women had a low
estrogen-receptor–level tumor but each had her observed cancer stage. The second sum
P. Cummings                                                                                  187
in the expression, after the line with only a division sign, is the sum of all estimated
risks if all women had a high estrogen-receptor–level tumor, again standardized to the
observed cancer-stage distribution. The first sum is divided by the second and the ln
taken of this ratio so that the ln of the risk ratio is estimated. I then estimated the risk
ratio, which is exp(lnrr), and the 95% upper and lower confidence limits for the risk
ratio, and used the display command to show these results for the last record by using
the subscript [ N]: risk ratio = 1.7, 95% CI is [1.1, 2.6].
    We can use simpler commands to estimate the risk ratio, but they do not provide
a CI. Still, these commands show how the risks and risk ratio may be estimated and
are shown below to clarify how Stata is using the regression estimates. After fitting the
logistic model, the commands are
      . replace low=0
      (48 real changes made)
      . predict risk0
      (option pr assumed; Pr(died))
      . summ risk0, meanonly
      . local avrisk0 = r(mean)
      . replace low=1
      (192 real changes made)
      . predict risk1
      (option pr assumed; Pr(died))
      . summ risk1, meanonly
      . local avrisk1 = r(mean)
      . local rr = `avrisk1´/`avrisk0´
      . display "Risk1 = " `avrisk1´ " Risk0 = " `avrisk0´ " Risk ratio = " `rr´
      Risk1 = .40087948 Risk0 = .23924549 Risk ratio = 1.6755989
    Risks for binomial outcomes can also be estimated after probit regression. In the
probit model, the outcome risk estimate applies the cumulative standard normal distri-
bution function (normal()) to the linear predictor, instead of the ln odds function used
in logistic regression:
      . #delimit ;
      delimiter now ;
      . predictnl lnrr = ln(
      >   sum(normal(_b[_cons]+_b[stage2]*stage2+_b[stage3]*stage3+_b[low]))
      >   /
      >   sum(normal(_b[_cons]+_b[stage2]*stage2+_b[stage3]*stage3)))
      >   , se(lnrr_se);
      . #delimit cr
      delimiter now cr
      . scalar rr = exp(lnrr[_N])
      . scalar upper = exp(lnrr[_N] + invnormal(1-.05/2)*lnrr_se[_N])
      . scalar lower = exp(lnrr[_N] - invnormal(1-.05/2)*lnrr_se[_N])
      . display "Risk ratio = " rr " 95% CI = " lower ", " upper
      Risk ratio = 1.6751332 95% CI = 1.0913484, 2.5711965
   Nelder (2001) has suggested that when a dichotomous outcome is common, the
complementary log-log regression model may fit the data well:
      . #delimit ;
      delimiter now ;
      . predictnl lnrr = ln(
      >   sum(1-exp(-exp(_b[_cons]+_b[stage2]*stage2+_b[stage3]*stage3+_b[low])))
      >   /
      >   sum(1-exp(-exp(_b[_cons]+_b[stage2]*stage2+_b[stage3]*stage3))))
      >   , se(lnrr_se);
      . #delimit cr
      delimiter now cr
      . scalar rr = exp(lnrr[_N])
      . scalar upper = exp(lnrr[_N] + invnormal(1-.05/2)*lnrr_se[_N])
      . scalar lower = exp(lnrr[_N] - invnormal(1-.05/2)*lnrr_se[_N])
      . display "Risk ratio = " rr " 95% CI = " lower ", " upper
      Risk ratio = 1.6652749 95% CI = 1.1009763, 2.5188013
   Hardin and Hilbe (2007, 147) note that if most subjects either have or do not have
the outcome, the complementary log-log and log-log models may fit better than logistic
or probit models. We can fit the log-log model using the glm command:
P. Cummings                                                                              189
                                      OIM
              died        exp(b)   Std. Err.     z    P>|z|    [95% Conf. Interval]
     . #delimit ;
     delimiter now ;
     . predictnl lnrr = ln(
     >   sum(exp(-exp(-(_b[_cons]+_b[stage2]*stage2+_b[stage3]*stage3+_b[low]))))
     >   /
     >   sum(exp(-exp(-(_b[_cons]+_b[stage2]*stage2+_b[stage3]*stage3)))))
     >   , se(lnrr_se);
     . #delimit cr
     delimiter now cr
     . scalar rr = exp(lnrr[_N])
     . scalar upper = exp(lnrr[_N] + invnormal(1-.05/2)*lnrr_se[_N])
     . scalar lower = exp(lnrr[_N] - invnormal(1-.05/2)*lnrr_se[_N])
     . display "Risk ratio = " rr " 95% CI = " lower ", " upper
     Risk ratio = 1.6312705 95% CI = 1.0545183, 2.5234682
      . scalar rr = exp(_b[low])/[(1-`p0´)+(`p0´*exp(_b[low]))]
      . scalar lower = exp(_b[low]-invnormal(1-.05/2)*_se[low])/[(1-`p0´)+
      > (`p0´*exp(_b[low]-invnormal(1-.05/2)*_se[low]))]
      . scalar upper = exp(_b[low]+invnormal(1-.05/2)*_se[low])/[(1-`p0´)+
      > (`p0´*exp(_b[low]+invnormal(1-.05/2)*_se[low]))]
      . display "Risk ratio = " rr " 95% CI = " lower ", " upper
      Risk ratio = 1.8933751 95% CI = 1.1180767, 2.7822097
10     Bootstrap CIs
In some examples above, approximately correct CIs were obtained using robust or delta
methods. Bootstrap methods can also be used for CIs. Here are commands to estimate
bootstrap CIs for the risk ratio by using a logistic model:
                         Observed                 Bootstrap
                           exp(b)        Bias     Std. Err.   [95% Conf. Interval]
    Stata’s bootstrap command simplifies the task of estimating bootstrap CIs by using
four methods: 1) normal, 2) percentile, 3) bias corrected, and 4) bias corrected and ac-
celerated. Other methods are available (Carpenter and Bithell 2000). For the risk ratios
estimated in this article, the choice among Stata’s four methods makes little difference.
But for some epidemiologic data, the normal and percentile methods should be used
with caution because they may have substantial coverage error (Efron and Tibshirani
1993; Carpenter and Bithell 2000; Greenland 2004b).
12     Summary
When the risk-ratio estimates in this article are rounded to one decimal, nearly all the
methods produced estimates of 1.6 or 1.7 (table 2). They also differed little with regard
to estimated CIs: the 95% lower bound was 1.0 or 1.1 and the upper bound, 2.3 to 2.6.
    The risk ratio that stands out as different came from the substitution method: risk
ratio = 1.9 and 95% CI is [1.1, 3.1]. The substitution method has nothing to recommend
it; it will usually produce estimates biased away from 1 when outcomes are common,
and in Stata it offers little advantage in terms of simplicity. Stata users who wish to
estimate an adjusted risk ratio have better methods that they can use, all of which are
fairly easy to implement.
192                                        Methods for estimating adjusted risk ratios
Table 2. Risk-ratio estimates for death within 5 years among 192 women with breast
cancer, comparing women with low estrogen-receptor–level tumors with women with
high estrogen-receptor–level tumors, adjusted for cancer stage at diagnosis. Results are
shown using the methods described in this article.
† Bias-corrected bootstrap CIs based upon 400001 replications. Not estimated for the inverse-variance
stratified method because the cs command does not return the pooled risk ratio from this method.
Not estimated for the maximum-likelihood version of the generalized linear model with a log link and
binomial distribution because convergence failed in many bootstrap samples. Convergence also failed in
100 bootstrap samples (0.025%) using Wacholder’s truncated method (binreg), 10 samples (0.0025%)
using the generalized linear model with a log link and Gaussian distribution, and 5 samples (0.00125%)
using the complementary log-log method.
‡ Akaike information criteria statistic for models fit using maximum likelihood. The statistic compares
the fitted model with a model that has only the outcome variable. In Stata, smaller Akaike information
criteria statistics indicate better fit.
P. Cummings                                                                        193
13     Acknowledgment
This work was supported by grant R49/CE000197-04 from the Centers for Disease
Control and Prevention, Atlanta, GA.
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P. Cummings                                                                          195
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