Anyone who has played pool knows that you have to call your shots before you make them. This rule is intended to decrease probability of "getting lucky" from just hitting the cue ball as hard as you can, expecting that the more it bounces around the table, the more likely it is that one of your many balls will fall through chance alone. Sinking a ball without first calling it is referred to coloquially as "slop" or a "slop shot".
The underlying logic is that you know best which shot you're MOST likely to successfully make, so not only does that increase the prior probability of a skilled versus a lucky shot (especially if it is a complex shot, such as one "off the rail"), but also it effectively reduces the number of chances the cue ball has to sink one of your balls without you losing your turn. It reduces those multiple chances to one single chance.
Likewise, a clinical trialist must focus on one "primary outcome" for two reasons: 1.) because preliminary data, if available, background knowledge, and logic will allow him to select the variable with the highest "pre-test probability" of causing the null hypothesis to be rejected, meaning that the post-test probability of the alternative hypothesis is enhanced; and 2.) because it reduces the probaility to find "significant" associations among multiple variables through chance alone. Today I came across a cute little experiment that drives this point home quite well. The abstract can be found here on pubmed: http://www.ncbi.nlm.nih.gov/pubmed/16895820?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum .
In it, the authors describe "dredging" a Canadian database and looking for correlations between astrological signs and various diagnoses. Significant associations were found between the Leo sign and gastrointestinal hemorrhage, and the Saggitarius sign and humerous fracture. With this "analogy of extremes" as I like to call them, you can clearly see how the failure to define a prospective primary endpoint can lead to statistical slop. (Nobody would have been able to predict a priori that it would be THOSE two diagnoses associated with THOSE two signs!) Failure to PROSPECTIVELY identify ONE primary endpoint led to multiple chances for chance associations. Moreover, because there were no preliminary data upon which to base a primary hypothesis, the prior probability of any given alternative hypothesis is markedly reduced, and thus the posterior probability of the alternative hypothesis remains low IN SPITE OF the statistically significant result.
It is for this very reason that "positive" or significant associations among non-primary endpoint variables in clinical trials are considered "hypothesis generating" rather than hypothesis confirming. Requiring additional studies of these associations as primary endpoints is like telling your slop shot partner in the pool hall "that's great, but I need to see you do that double rail shot again to believe that it's skill rather than luck."
Reproducibility of results is indeed the hallmark of good science.
Showing posts with label multiple comparisons. Show all posts
Showing posts with label multiple comparisons. Show all posts
Saturday, March 14, 2009
Monday, August 20, 2007
Prophylactic Cranial Irradiation: a matter of blinding, ascertainment, side effects, and preferences
Slotman et al (August 16 issue of NEJM: http://content.nejm.org/cgi/content/short/357/7/664) report a multicenter RCT of prophylactic cranial irradiation for extensive small cell carcinoma of the lung and conclude that it not only reduces symptomatic brain metastases, but also prolongs progression-free and overall survival. This is a well designed and conducted non-industry-sponsored RCT, but several aspects of the trial warrant scrutiny and temper my enthusiasm for this therapy. Among them:
The trial is not blinded (masked is a more sensitive term) from a patient perspective and no effort was made to create a sham irradiation procedure. While unintentional unmasking due to side effects may have limited the effectiveness of a sham procedure, it may not have rendered it entirely ineffective. This issue is of importance because meeting the primary endpoint was contingent on patient symptoms, and a placebo effect may have impacted participants’ reporting of symptoms. Some investigators have gone to great lengths to tease out placebo effects using sham procedures, and the results have been surprising (e.g., knee arthroscopy; see: https://content.nejm.org/cgi/content/abstract/347/2/81?ck=nck).
We are not told if investigators, the patient’s other physicians, radiologists, and statisticians were masked to the treatment assignment. Lack of masking may have led to other differences in patient management, or to differences in the threshold for ordering CT/MRI scans. We are not told about the number of CT/MRI scans in each group. In a nutshell: possible ascertainment bias (see http://www.consort-statement.org/?o=1123).
There are several apparently strong trends in QOL assessments, but we are not told what direction they are in. Significant differences in these scores were unlikely to be found as the deck was stacked when the trial was designed: p<0.01 was required for significance of QOL assessments. While this is justified because of multiple comparisons, it seems unfair to make the significance level for side effects more conservative than that for the primary outcome of interest (think Vioxx here). The significance level required for secondary endpoints (progression-free and overall survival) was not lowered to account for multiple comparisons. Moreover, more than half of QOL assessments were missing by 9 months, so this study is underpowered to detect differences in QOL. It is therefore all the more important to know the direction of the trends that are reported.
The authors appear to “gloss over” the significant side effects associated with this therapy. It made some subjects ill.
If we are willing to accept that overall survival is improved by this therapy (I’m personally circumspect about this for the above reasons) the bottom line for patients will be whether they would prefer on average 5 additional weeks of life with nausea, vomiting weight loss, fatigue, anorexia, and leg weakness to 5 fewer weeks of life without these symptoms. I think I know what choice many will make, and our projection bias may lead us to make inaccurate predictions of their choices (see Lowenstein, Medical Decision Making, Jan/Feb 2005: http://mdm.sagepub.com/cgi/content/citation/25/1/96).
The authors state in the concluding paragraph:
“Prophylactic cranial irradiation should be part of standard care for all patients with small-cell lung cancer who have a response to initial chemotherapy, and it should be part of the standard treatment in future studies involving these patients.”
I think the decision to use this therapy is one that only patients are justified making. At least now we have reasonably good data to help them inform their choice.
The trial is not blinded (masked is a more sensitive term) from a patient perspective and no effort was made to create a sham irradiation procedure. While unintentional unmasking due to side effects may have limited the effectiveness of a sham procedure, it may not have rendered it entirely ineffective. This issue is of importance because meeting the primary endpoint was contingent on patient symptoms, and a placebo effect may have impacted participants’ reporting of symptoms. Some investigators have gone to great lengths to tease out placebo effects using sham procedures, and the results have been surprising (e.g., knee arthroscopy; see: https://content.nejm.org/cgi/content/abstract/347/2/81?ck=nck).
We are not told if investigators, the patient’s other physicians, radiologists, and statisticians were masked to the treatment assignment. Lack of masking may have led to other differences in patient management, or to differences in the threshold for ordering CT/MRI scans. We are not told about the number of CT/MRI scans in each group. In a nutshell: possible ascertainment bias (see http://www.consort-statement.org/?o=1123).
There are several apparently strong trends in QOL assessments, but we are not told what direction they are in. Significant differences in these scores were unlikely to be found as the deck was stacked when the trial was designed: p<0.01 was required for significance of QOL assessments. While this is justified because of multiple comparisons, it seems unfair to make the significance level for side effects more conservative than that for the primary outcome of interest (think Vioxx here). The significance level required for secondary endpoints (progression-free and overall survival) was not lowered to account for multiple comparisons. Moreover, more than half of QOL assessments were missing by 9 months, so this study is underpowered to detect differences in QOL. It is therefore all the more important to know the direction of the trends that are reported.
The authors appear to “gloss over” the significant side effects associated with this therapy. It made some subjects ill.
If we are willing to accept that overall survival is improved by this therapy (I’m personally circumspect about this for the above reasons) the bottom line for patients will be whether they would prefer on average 5 additional weeks of life with nausea, vomiting weight loss, fatigue, anorexia, and leg weakness to 5 fewer weeks of life without these symptoms. I think I know what choice many will make, and our projection bias may lead us to make inaccurate predictions of their choices (see Lowenstein, Medical Decision Making, Jan/Feb 2005: http://mdm.sagepub.com/cgi/content/citation/25/1/96).
The authors state in the concluding paragraph:
“Prophylactic cranial irradiation should be part of standard care for all patients with small-cell lung cancer who have a response to initial chemotherapy, and it should be part of the standard treatment in future studies involving these patients.”
I think the decision to use this therapy is one that only patients are justified making. At least now we have reasonably good data to help them inform their choice.
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