tag:blogger.com,1999:blog-53761393226965034422017-04-22T11:43:40.490-05:00Statistical ThinkingThis blog is devoted to statistical thinking and its impact on science and everyday life. Emphasis is given to maximizing the use of information, avoiding statistical pitfalls, describing problems caused by the frequentist approach to statistical inference, describing advantages of Bayesian and likelihood methods, and discussing intended and unintended differences between statistics and data science. I'll also cover regression modeling strategies, clinical trials, and drug evaluation.Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.comBlogger15125tag:blogger.com,1999:blog-5376139322696503442.post-36233537246790302852017-04-08T08:36:00.001-05:002017-04-09T13:59:13.604-05:00Statistical Errors in the Medical LiteratureAs Doug Altman famously wrote in his <a href="http://www.bmj.com/content/308/6924/283">Scandal of Poor Medical Research</a> in BMJ in 1994, the quality of how statistical principles and analysis methods are applied in medical research is quite poor. According to Doug and to many others such as <a href="http://blogs.bmj.com/bmj/2014/01/31/richard-smith-medical-research-still-a-scandal/">Richard Smith</a>, the problems have only gotten worse. The purpose of this blog article is to contain a running list of new papers in major medical journals that are statistically problematic, based on my random encounters with the literature.<br /><br />One of the most pervasive problems in the medical literature (and in other subject areas) is misuse and misinterpretation of p-values as detailed <a href="http://www.fharrell.com/2017/02/a-litany-of-problems-with-p-values.html">here</a>, and chief among these issues is perhaps the <a href="http://www.bmj.com/content/311/7003/485">absence of evidence is not evidence of absence</a> error written about so clearly by Altman and Bland. The following thought will likely rattle many biomedical researchers but I've concluded that most of the gross misinterpretation of large p-values by falsely inferring that a treatment is not effective is caused by (1) the investigators not being brave enough to conclude "We haven't learned anything from this study", i.e., they feel compelled to believe that their investments of time and money must be worth something, (2) journals accepting such papers without demanding a proper statistical interpretation in the conclusion. One example of proper wording would be "This study rules out, with 0.95 confidence, a reduction in the odds of death that is more than by a factor of 2." Ronald Fisher, when asked how to interpret a large p-value, said "Get more data."<br /><br />Adoption of Bayesian methods would <a href="http://www.fharrell.com/2017/02/my-journey-from-frequentist-to-bayesian.html">solve many problems</a> including this one. Whether a p-value is small or large a Bayesian can compute the posterior probability of similarity of outcomes of two treatments (e.g., Prob(0.85 < odds ratio < 1/0.85)), and the researcher will often find that this probability is not large enough to draw a conclusion of similarity. <span style="color: blue;">On the other hand, what if even under a skeptical prior distribution the Bayesian posterior probability of efficacy were 0.8 in a "negative" trial? Would you choose for yourself the standard therapy when it had a 0.2 chance of being better than the new drug? [Note: I am not talking here about regulatory decisions.] Imagine a Bayesian world where it is standard to report the results for the primary endpoint using language such as:</span><br /><br /><ul><li><span style="color: blue;">The probability of any efficacy is 0.94 (so the probability of non-efficacy is 0.06).</span></li><li><span style="color: blue;">The probability of efficacy greater than a factor of 1.2 is 0.78 (odds ratio < 1/1.2).</span></li><li><span style="color: blue;">The probability of similarity to within a factor of 1.2 is 0.3.</span></li><li><span style="color: blue;">The probability that the true odds ratio is between [0.6, 0.99] is 0.95 (credible interval; doesn't use the long-run tendency of confidence intervals to include the true value for 0.95 of confidence intervals computed).</span></li></ul><br /><span style="color: blue;">In a so-called "negative" trial we frequently see the phrase "treatment B was not significantly different from treatment A" without thinking out how little information that carries. Was the power really adequate? Is the author talking about an observed statistic (probably yes) or the true unknown treatment effect? Why should we care more about statistical significance than clinical significance? The phrase "was not significantly different" seems to be a way to avoid the real issues of interpretation of large p-values.</span><br /><br />Since my #1 area of study is statistical modeling, especially predictive modeling, I pay a lot of attention to model development and model validation as done in the medical literature, and I routinely encounter published papers where the authors do not have basic understanding of the statistical principles involved. This seems to be especially true when a statistician is not among the paper's authors. I'll be commenting on papers in which I encounter statistical modeling, validation, or interpretation problems.<br /><br /><h3>Misinterpration of P-values and of Main Study Results</h3>One of the most problematic examples I've seen is in the March 2017 paper <a href="http://www.nejm.org/doi/full/10.1056/nejmoa1616218#t=article">Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery</a> by Rajenda Mehta in the New England Journal of Medicine. The study was designed to detect a miracle - a 35% relative odds reduction with drug compared to placebo, and used a power requirement of only 0.8 (type II error a whopping 0.2). [The study also used some questionable alpha-spending that Bayesians would find quite odd.] For the primary endpoint, the adjusted odds ratio was 1.00 with 0.99 confidence interval [0.66, 1.54] and p=0.98. Yet the authors concluded "Levosimendan was not associated with a rate of the composite of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among high-risk patients undergoing cardiac surgery with the use of cardiopulmonary bypass." Their own data are consistent with a 34% reduction (as well as a 54% increase)! Almost nothing was learned from this underpowered study. It may have been too disconcerting for the authors and the journal editor to have written "We were only able to rule out a massive benefit of drug." [Note: two treatments can have agreement in outcome probabilities by chance just as they can have differences by chance.] It would be interesting to see the Bayesian posterior probability that the true unknown odds ratio is in [0.85, 1/0.85].<br /><br />The primary endpoint is the union of death, dialysis, MI, or use of a cardiac assist device. This counts these four endpoints as equally bad. An ordinal response variable would have yielded more statistical information/precision and perhaps increased power. And instead of dealing with multiplicity issues and alpha-spending, the multiple endpoints could have been dealt with more elegantly with a Bayesian analysis. For example, one could easily compute the joint probability that the odds ratio for the primary endpoint is less than 0.8 and the odds ratio for the secondary endpoint is less than 1 [the secondary endpoint was death or assist device and and is harder to demonstrate because of its lower incidence, and is perhaps more of a "hard endpoint"]. In the Bayesian world of forward directly relevant probabilities there is no need to consider multiplicity. There is only a need to state the assertions for which one wants to compute current probabilities.<br /><br />The paper also contains inappropriate assessments of interactions with treatment using subgroup analysis with arbitrary cutpoints on continuous baseline variables and failure to adjust for other main effects when doing the subgroup analysis.<br /><br />This paper had a fine statistician as a co-author. I can only conclude that the pressure to avoid disappointment with a conclusion of spending a lot of money with little to show for it was in play.<br /><br />Why was such an underpowered study launched? Why do researchers attempt "hail Mary passes"? Is a study that is likely to be futile fully ethical? Do medical journals allow this to happen because of some vested interest?<br /><h4><span style="color: blue;">Similar Examples</span></h4><span style="color: blue;">Perhaps the above example is no worse than many. Examples of "absence of evidence" misinterpretations abound. Consider the <a href="http://jamanetwork.com/journals/jama/article-abstract/2612911">JAMA</a> paper by Kawazoe et al published 2017-04-04. They concluded that "<span style="font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif; font-size: 16px;">Mortality at 28 days was not significantly different in the dexmedetomidine group vs the control group (19 patients [22.8%] vs 28 patients [30.8%]; hazard ratio, 0.69; 95% CI, 0.38-1.22; </span><i style="box-sizing: inherit; font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif; font-size: 16px;">P</i><span style="font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif; font-size: 16px;"> = .20)." The point estimate was a reduction in hazard of death by 31% and the data are consistent with the reduction being as large as 62%!</span></span><br /><span style="font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif; font-size: 16px;"><span style="color: blue;"><br /></span></span><span style="color: blue;"><span style="font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif; font-size: 16px;">Or look at <a href="http://jamanetwork.com/journals/jama/article-abstract/2613159">this</a> 2017-03-21 JAMA article in which the authors concluded "</span><span style="font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif; font-size: 16px;">Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D</span><sub style="box-sizing: inherit; font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif;">3</sub><span style="font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif; font-size: 16px;"> and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years." even though the observed hazard ratio was 0.7, with lower confidence limit of a whopping 53% reduction in the incidence of cancer. And the 0.7 was an unadjusted hazard ratio; the hazard ratio could well have been more impressive had covariate adjustment been used to account for outcome heterogeneity within each treatment arm.</span></span><br /><span style="font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif; font-size: 16px;"><span style="color: blue;"><br /></span></span><span style="color: #333333; font-family: "Guardian TextSans Web", "Helvetica Neue", Helvetica, Arial, sans-serif; font-size: 16px;"><br /></span><div><br /></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com15tag:blogger.com,1999:blog-5376139322696503442.post-53483888705676718762017-03-16T11:53:00.004-05:002017-03-27T07:32:40.018-05:00Subjective Ranking of Quality of Research by Subject Matter AreaWhile being engaged in biomedical research for a few decades and watching reproducibility of research as a whole, I've developed my own ranking of reliability/quality/usefulness of research across several subject matter areas. This list is far from complete. Let's start with a subjective list of what I perceive as the areas in which published research is least likely to be both true and useful. The following list is ordered in ascending order of quality, with the most problematic area listed first. You'll notice that there is a vast number of areas not listed for which I have minimal experience.<br /><span style="color: blue;"><br /></span><span style="color: blue;">Some excellent research is done in all subject areas. This list is based on my perception of the <b>proportion</b> of publications in the indicated area that are rigorously scientific, reproducible, and useful.</span><br /><h4>Subject Areas With Least Reliable/Reproducible/Useful Research</h4><div><ol><li>any area where there is no pre-specified statistical analysis plan and the analysis can change on the fly when initial results are disappointing</li><li>behavioral psychology</li><li>studies of corporations to find characteristics of "winners"; regression to the mean kicks in making predictions useless for changing your company</li><li>animal experiments on fewer than 30 animals</li><li><span style="color: blue;">discovery genetics not making use of biology while doing large-scale variant/gene screening</span></li><li>nutritional epidemiology</li><li>electronic health record research reaching clinical conclusions without understanding confounding by indication and other limitations of data</li><li>pre-post studies with no randomization</li><li>non-nutritional epidemiology <span style="color: blue;">not having a fully pre-specified statistical analysis plan</span> <span style="color: blue;">[few epidemiology papers use state-of-the-art statistical methods and have a sensitivity analysis related to unmeasured confounders]</span></li><li>prediction studies based on dirty and inadequate data</li><li>personalized medicine</li><li>biomarkers</li><li>observational treatment comparisons that do not qualify for the second list (below)</li><li>small adaptive dose-finding cancer trials (3+3 etc.)</li></ol><h4>Subject Areas With Most Reliable/Reproducible/Useful Research</h4><div>The most reliable and useful research areas are listed first. All of the following are assumed to (1) have a prospective pre-specified statistical analysis plan and (2) purposeful prospective quality-controlled data acquisition (yes this applies to high-quality non-randomized observational research).</div><ol><li>randomized crossover studies</li><li>multi-center randomized experiments</li><li>single-center randomized experiments <span style="color: blue;">with non-overly-optimistic sample sizes</span></li><li>adaptive randomized clinical trials with large sample sizes</li><li><span style="color: blue;">physics</span></li><li><span style="color: blue;">pharmaceutical industry research that is overseen by FDA</span></li><li>cardiovascular research</li><li>observational research <span style="color: blue;">[however only a very small minority of observational research projects have a prospective analysis plan and high enough data quality to qualify for this list]</span></li></ol><div><br /></div><h4><span style="color: blue;">Some Suggested Remedies</span></h4></div><div><span style="color: blue;">Peer review of research grants and manuscripts is done primarily by experts in the subject matter area under study. Most journal editors and grant reviewers are not expert in biostatistics. Every grant application and submitted manuscript should undergo rigorous methodologic peer review by methodologic experts such as biostatisticians and epidemiologists. All data analyses should be driven by a prospective statistical analysis plan, and the entire self-contained data manipulation and analysis code should be submitted to journals so that potential reproducibility and adherence to the statistical analysis plan can be confirmed. Readers should have access to the data in most cases and should be able to reproduce all study findings using the authors' code, plus run their own analyses on the authors' data to check robustness of findings.</span><br /><span style="color: blue;"><br /></span><span style="color: blue;">Medical journals are reluctant to (1) publish critical letters to the editor and (2) retract papers. This has to change.</span><br /><span style="color: blue;"><br /></span><span style="color: blue;">In academia, too much credit is still given to the quantity of publications and not to their quality and reproducibility. This too must change. The pharmaceutical industry has FDA to validate their research. The NIH does not serve this role for academia.</span><br /><span style="color: blue;"><br /></span><span style="color: blue;">Rochelle Tractenberg, Chair of the American Statistical Association Committee on Professional Ethics and a biostatistician at Georgetown University said in a 2017-02-22 interview with <i>The Australian</i> that many questionable studies would not have been published had formal statistical reviews been done. When she reviews a paper she starts with the premise that the statistical analysis was incorrectly executed. She stated that "Bad statistics is bad science."</span><br /><span style="color: blue;"><br /></span></div><div></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com14tag:blogger.com,1999:blog-5376139322696503442.post-27641736403136926482017-03-01T07:30:00.002-06:002017-03-01T07:30:36.950-06:00Damage Caused by Classification Accuracy and Other Discontinuous Improper Accuracy Scoring RulesIn <a href="http://www.fharrell.com/2017/01/classification-vs-prediction.html">this article</a> I discussed the many advantages or probability estimation over classification. Here I discuss a particular problem related to classification, namely the harm done by using improper accuracy scoring rules. Accuracy scores are used to drive feature selection, parameter estimation, and for measuring predictive performance on models derived using any optimization algorithm. For this discussion let Y denote a no/yes false/true 0/1 event being predicted, and let Y=0 denote a non-event and Y=1 the event occurred.<br /><br />As discussed <a href="https://en.wikipedia.org/wiki/Scoring_rule">here</a> and <a href="http://psiexp.ss.uci.edu/research/papers/MerkleSteyvers.pdf">here</a>, a <i>proper accuracy scoring</i> rule is a metric applied to probability forecasts. It is a metric that is optimized when the forecasted probabilities are identical to the true outcome probabilities. A <i>continuous</i> accuracy scoring rule is a metric that makes full use of the entire range of predicted probabilities and does not have a large jump because of an infinitesimal change in a predicted probability. The two most commonly used proper scoring rules are the quadratic error measure, i.e., mean squared error or <a href="https://en.wikipedia.org/wiki/Brier_score">Brier score</a>, and the logarithmic scoring rule, which is a linear translation of the log likelihood for a binary outcome model (Bernoulli trials). The logarithmic rule gives more credit to extreme predictions that are "right", but a single prediction of 1.0 when Y=0 or 0.0 when Y=1 will result in infinity no matter how accurate were all the other predictions. Because of the optimality properties of maximum likelihood estimation, the logarithmic scoring rule is in a sense the gold standard, but we more commonly use the Brier score because of its easier interpretation and its ready decomposition into various metrics measuring calibration-in-the-small, calibration-in-the-large, and discrimination.<br /><br /><i>Classification accuracy</i> is an improper scoring rule. It implicitly or explicitly uses thresholds for probabilities, and moving a prediction from 0.0001 below the threshold to 0.0001 above the thresholds results in a full accuracy change of 1/N. Classification accuracy is also an improper scoring rule. It can be optimized by choosing the wrong predictive features and giving them the wrong weights. This is best shown by a simple example that appears in <a href="http://biostat.mc.vanderbilt.edu/ClinStat">Biostatistics for Biomedical Research</a> Chapter 18 in which 400 simulated subjects have an overall fraction of Y=1 of 0.57. Consider the use of binary logistic regression to predict the probability that Y=1 given a certain set of covariates, and classify a subject as having Y=1 if the predicted probability exceeds 0.5. We simulate values of age and sex and simulate binary values of Y according to a logistic model with strong age and sex effects; the true log odds of Y=1 are <span style="font-family: "courier new" , "courier" , monospace; font-size: x-small;">(age-50)*.04 + .75*(sex=m)</span>. Fit four binary logistic models in order: a model containing only age as a predictor, one containing only sex, one containing both age and sex, and a model containing no predictors (i.e., it only has an intercept parameter). The results are in the following table:<br /><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://4.bp.blogspot.com/-SlRTo_OLpZA/WLQjYnNwGTI/AAAAAAAAI3Q/WFauwVRfBeYYlLfRL04Z29S6b0uLbWqTACLcB/s1600/z.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="233" src="https://4.bp.blogspot.com/-SlRTo_OLpZA/WLQjYnNwGTI/AAAAAAAAI3Q/WFauwVRfBeYYlLfRL04Z29S6b0uLbWqTACLcB/s320/z.png" width="320" /></a></div>Both the gold standard likelihood ratio chi-square statistic and the improper pure discrimination c-index (AUROC) indicate that both age and sex are important predictors of Y. Yet the highest proportion correct (classification accuracy) occurs when sex is ignored. According to the improper score, the sex variable has negative information. It is telling that a model that predicted Y=1 for every observation, i.e., one that completely ignored age and sex and only has the intercept in the model, would be 0.573 accurate, only slightly above the accuracy of using sex alone to predict Y.<br /><br />The use of a discontinuous improper accuracy score such as proportion "classified" "correctly" has led to countless misleading findings in bioinformatics, machine learning, and data science. In some extreme cases the machine learning expert failed to note that their claimed predictive accuracy was less than that achieved by ignoring the data, e.g., by just predicting Y=1 when the observed prevalence of Y=1 was 0.98 whereas their extensive data analysis yielded an accuracy of 0.97. As discusssed <a href="http://www.fharrell.com/2017/01/classification-vs-prediction.html">here</a>, fans of "classifiers" sometimes subsample from observations in the most frequent outcome category (here Y=1) to get an artificial 50/50 balance of Y=0 and Y=1 when developing their classifier. Fans of such deficient notions of accuracy fail to realize that their classifier will not apply to a population when a much different prevalence of Y=1 than 0.5.<br /><br /><i>Sensitivity</i> and <i>specificity</i> are one-sided or conditional versions of classification accuracy. As such they are also discontinuous improper accuracy scores, and optimizing them will result in the wrong model.<br /><br /><a href="http://biostat.mc.vanderbilt.edu/rms">Regression Modeling Strategies</a> Chapter 10 goes into more problems with classification accuracy, and discusses many measures of the quality of probability estimates. The text contains suggested measures to emphasize such as Brier score, pseudo R-squared (a simple function of the logarithmic scoring rule), c-index, and especially smooth nonparametric calibration plots to demonstrate absolute accuracy of estimated probabilities.<br /><br /><br />Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com3tag:blogger.com,1999:blog-5376139322696503442.post-2350316649043495732017-02-19T10:23:00.000-06:002017-02-20T14:13:02.175-06:00My Journey From Frequentist to Bayesian Statistics<div style="text-align: justify;">If I had been taught Bayesian modeling before being taught the frequentist paradigm, I'm sure I would have always been a Bayesian. I started becoming a Bayesian about 1994 because of an <a href="http://www.citeulike.org/user/harrelfe/article/13264891">influential paper</a> by David Spiegelhalter and because I worked in the same building at Duke University as Don Berry. Two other things strongly contributed to my thinking: difficulties explaining p-values and confidence intervals (especially the latter) to clinical researchers, and difficulty of learning group sequential methods in clinical trials. When I talked with Don and learned about the flexibility of the Bayesian approach to clinical trials, and saw Spiegelhalter's embrace of Bayesian methods because of its problem-solving abilities, I was hooked. [Note: I've heard Don say that he became Bayesian after multiple attempts to teach statistics students the exact definition of a confidence interval. He decided the concept was defective.]</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">At the time I was working on clinical trials at Duke and started to see that multiplicity adjustments were arbitrary. This started with a clinical trial coordinated by Duke in which low dose and high dose of a new drug were to be compared to placebo, using an alpha cutoff of 0.03 for each comparison to adjust for multiplicity. The comparison of high dose with placebo resulted in a p-value of 0.04 and the trial was labeled completely "negative" which seemed problematic to me. [Note: the p-value was two-sided and thus didn't give any special "credit" for the treatment effect coming out in the right direction.]</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">I began to see that the hypothesis testing framework wasn't always the best approach to science, and that in biomedical research the typical hypothesis was an artificial construct designed to placate a reviewer who believed that an NIH grant's specific aims must include null hypotheses. I saw the contortions that investigators went through to achieve this, came to see that questions are more relevant than hypotheses, and estimation was even more important than questions. With Bayes, estimation is emphasized. I very much like Bayesian modeling instead of hypothesis testing. I saw that a large number of clinical trials were incorrectly interpreted when p>0.05 because the investigators involved failed to realize that a p-value can only provide evidence against a hypothesis. Investigators are motivated by "we spent a lot of time and money and must have gained something from this experiment." The classic "<a href="http://www.bmj.com/content/311/7003/485">absence of evidence is not evidence of absence</a>" error results, whereas with Bayes it is easy to estimate the probability of similarity of two treatments. Investigators will be surprised to know how little we have learned from clinical trials that are not huge when p>0.05.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">I listened to many discussions of famous clinical trialists debating what should be the primary endpoint in a trial, the co-primary endpoint, the secondary endpoints, co-secondary endpoints, etc. This was all because of their paying attention to alpha-spending. I realized this was all a game.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">I came to not believe in the possibility of infinitely many repetitions of identical experiments, as required to be envisioned in the frequentist paradigm. When I looked more thoroughly into the multiplicity problem, and sequential testing, and I looked at Bayesian solutions, I became more of a believer in the approach. I learned that posterior probabilities have a simple interpretation independent of the stopping rule and frequency of data looks. I got involved in working with the FDA and then consulting with pharmaceutical companies, and started observing how multiple clinical endpoints were handled. I saw a closed testing procedures where a company was seeking a superiority claim for a new drug, and if there was insufficient evidence for such a claim, they wanted to seek a non-inferiority claim on another endpoint. They developed a closed testing procedure that when diagrammed truly looked like a train wreck. I felt there had to be a better approach, so I sought to see how far posterior probabilities could be pushed. I found that with MCMC simulation of Bayesian posterior draws I could quite simply compute probabilities such as P(any efficacy), P(efficacy more than trivial), P(non-inferiority), P(efficacy on endpoint A and on either endpoint B or endpoint C), and P(benefit on more than 2 of 5 endpoints). I realized that frequentist multiplicity problems came from the chances you give data to be more extreme, not from the chances you give assertions to be true.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">I enjoy the fact that posterior probabilities define their own error probabilities, and that they count not only inefficacy but also harm. If P(efficacy)=0.97, P(no effect or harm)=0.03. This is the "regulator's regret", and type I error is not the error of major interest (is it really even an 'error'?). One minus a p-value is P(data in general are less extreme than that observed if H0 is true) which is the probability of an event I'm not that interested in.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">The extreme amount of time I spent analyzing data led me to understand other problems with the frequentist approach. Parameters are either in a model or not in a model. We test for interactions with treatment and hope that the p-value is not between 0.02 and 0.2. We either include the interactions or exclude them, and the power for the interaction test is modest. Bayesians have a prior for the differential treatment effect and can easily have interactions "half in" the model. Dichotomous irrevocable decisions are at the heart of many of the statistical modeling problems we have today. I really like penalized maximum likelihood estimation (which is really empirical Bayes) but once we have a penalized model all of our frequentist inferential framework fails us. No one can interpret a confidence interval for a biased (shrunken; penalized) estimate. On the other hand, the Bayesian posterior probability density function, after shrinkage is accomplished using skeptical priors, is just as easy to interpret as had the prior been flat. For another example, consider a categorical predictor variable that we hope is predicting in an ordinal (monotonic) fashion. We tend to either model it as ordinal or as completely unordered (using k-1 indicator variables for k categories). A Bayesian would say "let's use a prior that favors monotonicity but allows larger sample sizes to override this belief."</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">Now that adaptive and sequential experiments are becoming more popular, and a formal mechanism is needed to use data from one experiment to inform a later experiment (a good example being the use of adult clinical trial data to inform clinical trials on children when it is difficult to enroll a sufficient number of children for the child data to stand on their own), Bayes is needed more than ever. It took me a while to realize something that is quite profound: A Bayesian solution to a simple problem (e.g., 2-group comparison of means) can be embedded into a complex design (e.g., adaptive clinical trial) <b>without modification</b>. Frequentist solutions require highly complex modifications to work in the adaptive trial setting.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">I met likelihoodist <a href="http://biostat.mc.vanderbilt.edu/JeffreyBlume">Jeffrey Blume</a> in 2008 and started to like the likelihood approach. It is more Bayesian than frequentist. I plan to learn more about this paradigm. </div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">Several readers have asked me how I could believe all this and publish a frequentist-based book such as <i>Regression Modeling Strategies</i>. There are two primary reasons. First, I started writing the book before I knew much about Bayes. Second, I performed a lot of simulation studies that showed that purely empirical model-building had a low chance of capturing clinical phenomena correctly and of validating on new datasets. I worked extensively with cardiologists such as Rob Califf, Dan Mark, Mark Hlatky, David Prior, and Phil Harris who give me the ideas for injecting clinical knowledge into model specification. From that experience I wrote <i>Regression Modeling Strategies</i> in the most Bayesian way I could without actually using specific Bayesian methods. I did this by emphasizing subject-matter-guided model specification. The section in the book about specification of interaction terms is perhaps the best example. When I teach the full-semester version of my course I interject Bayesian counterparts to many of the techniques covered.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">There are challenges in moving more to a Bayesian approach. The ones I encounter most frequently are:</div><ol><li style="text-align: justify;">Teaching clinical trialists to embrace Bayes when they already do in spirit but not operationally. Unlearning things is much more difficult than learning things.</li><li style="text-align: justify;">How to work with sponsors, regulators, and NIH principal investigators to specify the (usually skeptical) prior up front, and to specify the amount of applicability assumed for previous data.</li><li style="text-align: justify;">What is a Bayesian version of the multiple degree of freedom "chunk test"? Partitioning sums of squares or the log likelihood into components, e.g., combined test of interaction and combined test of nonlinearities, is very easy and natural in the frequentist setting.</li><li style="text-align: justify;">How do we specify priors for complex entities such as the degree of monotonicity of the effect of a continuous predictor in a regression model? The Bayesian approach to this will ultimately be more satisfying, but operationalizing this is not easy.</li></ol><div style="text-align: justify;">With new tools such as <a href="http://mc-stan.org/">Stan</a> and well written accessible books such as <a href="http://www.citeulike.org/user/harrelfe/article/14172337">Kruschke's</a> it's getting to be easier to be Bayesian each day. The R <a href="https://cran.r-project.org/web/packages/brms">brms</a> package, which uses Stan, makes a large class of regression models even more accessible.<br /><br /><br /><br /><a name='more'></a>See the following for discussions about this article that are not on this blog.<br /><br /><ul><li>https://news.ycombinator.com/item?id=13684429</li></ul></div><div style="text-align: justify;"><br /></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com35tag:blogger.com,1999:blog-5376139322696503442.post-21027066199349958892017-02-05T09:43:00.000-06:002017-02-26T06:48:43.203-06:00Interactive Statistical Graphics: Showing More By Showing LessVersion 4 of the R <a href="http://biostat.mc.vanderbilt.edu/Hmisc">Hmisc</a> packge and version 5 of the R <a href="http://biostat.mc.vanderbilt.edu/Rrms">rms</a> package interfaces with interactive <a href="https://plot.ly/r/">plotly</a> graphics, which is an interface to the D3 javascript graphics library. This allows various results of statistical analyses to be viewed interactively, with pre-programmed drill-down information. More examples will be added here. We start with a video showing a new way to display survival curves. <br /><br />Note that plotly graphics are best used with RStudio Rmarkdown html notebooks, and are distributed to reviewers as self-contained (but somewhat large) html files. Printing is discouraged, but possible, using snapshots of the interactive graphics.<br /><br />Concerning the second bullet point below, boxplots have a high ink:information ratio and hide bimodality and other data features. Many statisticians prefer to use dot plots and violin plots. I liked those methods for a while, then started to have trouble with the choice of a smoothing bandwidth in violin plots, and found that dot plots do not scale well to very large datasets, whereas spike histograms are useful for all sample sizes. Users of dot charts have to have a dot stand for more than one observation if N is large, and I found the process too arbitrary. For spike histograms I typically use 100 or 200 bins. When the number of distinct data values is below the specified number of bins, I just do a frequency tabulation for all distinct data values, rounding only when two of the values are very close to each other. A spike histogram approximately reduces to a rug plot when there are no ties in the data, and I very much like rug plots.<br /><br /><ul><li>rms survplotp <a href="https://youtu.be/EoIB_Obddrk">video</a>: plotting survival curves</li><li>Hmisc histboxp <a href="http://data.vanderbilt.edu/fh/R/Hmisc/examples.nb.html#better_demonstration_of_boxplot_replacement">interactive html example</a>: spike histograms plus selected quantiles, mean, and Gini's mean difference - replacement for boxplots - show all the data! Note bimodal distributions and zero blood pressure values for patients having a cardiac arrest.</li></ul><div class="separator" style="clear: both; text-align: center;"><a href="http://3.bp.blogspot.com/-hsRxcCS4HMs/WKTJXR7PO5I/AAAAAAAAIVo/9bzR4N5u_aUCHWJ2m2kqNvpGLKhQzfDcACK4B/s1600/histboxp.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="107" src="https://3.bp.blogspot.com/-hsRxcCS4HMs/WKTJXR7PO5I/AAAAAAAAIVo/9bzR4N5u_aUCHWJ2m2kqNvpGLKhQzfDcACK4B/s320/histboxp.png" width="320" /></a></div><div><br /></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com3tag:blogger.com,1999:blog-5376139322696503442.post-58368734038944632682017-02-05T08:39:00.000-06:002017-02-05T09:00:02.045-06:00A Litany of Problems With p-valuesIn my opinion, null hypothesis testing and p-values have done significant harm to science. The purpose of this note is to catalog the many problems caused by p-values. As readers post new problems in their comments, more will be incorporated into the list, so this is a work in progress.<br /><br />The American Statistical Association has done a great service by issuing its <a href="http://www.amstat.org/asa/files/pdfs/P-ValueStatement.pdf">Statement on Statistical Significance and P-values</a>. Now it's time to act. To create the needed motivation to change, we need to fully describe the depth of the problem.<br /><br />It is important to note that no statistical paradigm is perfect. Statisticians should choose paradigms that solve the greatest number of real problems and have the fewest number of faults. This is why I believe that the Bayesian and likelihood paradigms should replace frequentist inference.<br /><br />Consider an assertion such as "the coin is fair", "treatment A yields the same blood pressure as treatment B", "B yields lower blood pressure than A", or "B lowers blood pressure at least 5mmHg before A." Consider also a compound assertion such as "A lowers blood pressure by at least 3mmHg and does not raise the risk of stroke."<br /><br /><h3>A. Problems With Conditioning</h3><div><ol><li>p-values condition on what is unknown (the assertion of interest; H<sub>0</sub>) and do not condition on what is known (the data).</li><li>This conditioning does not respect the flow of time and information; p-values are backward probabilities.</li></ol><div><h3>B. Indirectness</h3></div><ol><li>Because of A above, p-values provide only indirect evidence and are problematic as evidence metrics. They are sometimes monotonically related to the evidence (e.g., when the prior distribution is flat) we need but are not properly calibrated for decision making.</li><li>p-values are used to bring indirect evidence against an assertion but cannot bring evidence in favor of the assertion. </li><li>As detailed <a href="http://www.fharrell.com/2017/01/null-hypothesis-significance-testing.html">here</a>, the idea of proof by contradiction is a stretch when working with probabilities, so trying to quantify evidence for an assertion by bringing evidence against its complement is on shaky ground.</li><li>Because of A, p-values are difficult to interpret and very few non-statisticians get it right. The best article on misinterpretations I've found is <a href="http://www.citeulike.org/user/harrelfe/article/14042559">here</a>.</li></ol><div><h3>C. Problem Defining the Event Whose Probability is Computed</h3></div><ol><li>In the continuous data case, the probability of getting a result as extreme as that observed with our sample is zero, so the p-value is the probability of getting a result <i>more extreme</i> than that observed. Is this the correct point of reference?</li><li>How does <i>more extreme</i> get defined if there are sequential analyses and multiple endpoints or subgroups? For sequential analyses do we consider planned analyses are analyses intended to be run even if they were not?</li></ol><div><h3>D. Problems Actually Computing p-values</h3></div><ol><li>In some discrete data cases, e.g., comparing two proportions, there is tremendous disagreement among statisticians about how p-values should be calculated. In a famous 2x2 table from an ECMO adaptive clinical trial, 13 p-values have been computed from the same data, ranging from 0.001 to 1.0. And many statisticians do not realize that Fisher's so-called "exact" test is not very accurate in many cases.</li><li>Outside of binomial, exponential, and normal (with equal variance) and a few other cases, p-values are actually very difficult to compute exactly, and many p-values computed by statisticians are of unknown accuracy (e.g., in logistic regression and mixed effects models). The more non-quadratic the log likelihood function the more problematic this becomes in many cases. </li><li>One can compute (sometimes requiring simulation) the type-I error of many multi-stage procedures, but actually computing a p-value that can be taken out of context can be quite difficult and sometimes impossible. One example: one can control the false discovery probability (incorrectly usually referred to as a rate), and ad hoc modifications of nominal p-values have been proposed, but these are not necessarily in line with the real definition of a p-value.</li></ol><div><h3>E. The Multiplicity Mess</h3></div><ol><li>Frequentist statistics does not have a recipe or blueprint leading to a unique solution for multiplicity problems, so when many p-values are computed, the way they are penalized for multiple comparisons results in endless arguments. A Bonferroni multiplicity adjustment is consistent with a Bayesian prior distribution specifying that the probability that all null hypotheses are true is a constant no matter how many hypotheses are tested. By contrast, Bayesian inference reflects the facts that P(A ∪ B) ≥ max(P(A), P(B)) and P(A ∩ B) ≤ min(P(A), P(B)) when A and B are assertions about a true effect.</li><li>There remains controversy over the choice of 1-tailed vs. 2-tailed tests. The 2-tailed test can be thought of as a multiplicity penalty for being potentially excited about either a positive effect or a negative effect of a treatment. But few researchers want to bring evidence that a treatment harms patients; a pharmaceutical company would not seek a licensing claim of harm. So when one computes the probability of obtaining an effect larger than that observed if there is no true effect, why do we too often ignore the sign of the effect and compute the (2-tailed) p-value?</li><li>Because it is a very difficult problem to compute p-values when the assertion is compound, researchers using frequentist methods do not attempt to provide simultaneous evidence regarding such assertions and instead rely on ad hoc multiplicity adjustments.</li><li>Because of A1, statistical testing with multiple looks at the data, e.g., in sequential data monitoring, is ad hoc and complex. Scientific flexibility is discouraged. The p-value for an early data look must be adjusted for future looks. The p-value at the final data look must be adjusted for the earlier inconsequential looks. Unblinded sample size re-estimation is another case in point. If the sample size is expanded to gain more information, there is a multiplicity problem and some of the methods commonly used to analyze the final data effectively discount the first wave of subjects. How can that make any scientific sense?</li><li>Most practitioners of frequentist inference do not understand that multiplicity comes from chances you give data to be extreme, not from chances you give true effects to be present.</li></ol><div><h3>F. Problems With Non-Trivial Hypotheses</h3></div><ol><li>It is difficult to test non-point hypotheses such as "drug A is similar to drug B".</li><li>There is no straightforward way to test compound hypotheses coming from logical unions and intersections. </li></ol><div><h3>G. Inability to Incorporate Context and Other Information</h3></div><ol><li>Because extraordinary claims require extraordinary evidence, there is a serious problem with the p-value's inability to incorporate context or prior evidence. A Bayesian analysis of the existence of ESP would no doubt start with a very skeptical prior that would require extraordinary data to overcome, but the bar for getting a "significant" p-value is fairly low. Frequentist inference has a greater risk for getting the direction of an effect wrong (see <a href="http://andrewgelman.com/">here</a> for more).</li><li>p-values are unable to incorporate outside evidence. As a converse to 1, strong prior beliefs are unable to be handled by p-values, and in some cases the results in a lack of progress. Nate Silver in <i>The Signal and the Noise</i> beautifully details how the conclusion that cigarette smoking causes lung cancer was greatly delayed (with a large negative effect on public health) because scientists (especially Fisher) were caught up in the frequentist way of thinking, dictating that only randomized trial data would yield a valid p-value for testing cause and effect. A Bayesian prior that was very strongly against the belief that smoking was causal is obliterated by the incredibly strong observational data. Only by incorporating prior skepticism could one make a strong conclusion with non-randomized data in the smoking-lung cancer debate.</li><li>p-values require subjective input from the producer of the data rather than from the consumer of the data.</li></ol><h3>H. Problems Interpreting and Acting on "Positive" Findings</h3><ol><li>With a large enough sample, a trivial effect can cause an impressively small p-value (statistical significance ≠ clinical significance).</li><li>Statisticians and subject matter researchers (especially the latter) sought a "seal of approval" for their research by naming a cutoff on what should be considered "statistically significant", and a cutoff of p=0.05 is most commonly used. Any time there is a threshold there is a motive to game the system, and gaming (p-hacking) is rampant. Hypotheses are exchanged if the original H<sub>0</sub> is not rejected, subjects are excluded, and because statistical analysis plans are not pre-specified as required in clinical trials and regulatory activities, researchers and their all-too-accommodating statisticians play with the analysis until something "significant" emerges.</li><li>When the p-value is small, researchers act as though the point estimate of the effect is a population value.</li><li>When the p-value is small, researchers believe that their conceptual framework has been validated. </li></ol><div><h3>I. Problems Interpreting and Acting on "Negative" Findings</h3><ol><li>Because of B2, large p-values are uninformative and do not assist the researcher in decision making (Fisher said that a large p-value means "get more data").</li></ol><div><br /></div></div><div></div></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com82tag:blogger.com,1999:blog-5376139322696503442.post-42968695135969555792017-01-27T07:03:00.002-06:002017-01-27T07:55:03.326-06:00Randomized Clinical Trials Do Not Mimic Clinical Practice, Thank GoodnessRandomized clinical trials (RCT) have long been held as the gold standard for generating evidence about the effectiveness of medical and surgical treatments, and for good reason. But I commonly hear clinicians lament that the results of RCTs are not generalizable to medical practice, primarily for two reasons:<br /><ol><li>Patients in clinical practice are different from those enrolled in RCTs</li><li>Drug adherence in clinical practice is likely to be lower than that achieved in RCTs, resulting in lower efficacy.</li></ol><div>Point 2 is hard to debate because RCTs are run under protocol and research personnel are watching and asking about patients' adherence. But point 1 is a misplaced worry in the majority of trials. The explanation requires getting to the heart of what RCTs are really intended to do: provide evidence for <b>relative</b> treatment effectiveness. There are some trials that provide evidence for both relative and absolute effectiveness. This is especially true when the efficacy measure employed is absolute as in measuring blood pressure reduction due to a new treatment. But many trials use binary or time-to-event endpoints and the resulting efficacy measure is on a relative scale such as the odds ratio or hazard ratio.</div><div><br /></div><div>RCTs of even drastically different patients can provide estimates of relative treatment benefit on odds or hazard ratio scales that are highly transportable. This is most readily seen in subgroup analyses provided by the trials themselves - so called forest plots that demonstrate remarkable constancy of relative treatment benefit. When an effect ratio is applied to a population with a much different risk profile, that relative effect can still fully apply. It is only likely that the absolute treatment benefit will change, and it is easy to estimate the absolute benefit (e.g., risk difference) for a patient given the relative benefit and the absolute baseline risk for the subject. This is covered in detail in <a href="http://biostat.mc.vanderbilt.edu/tmp/bbr.pdf">Biostatistics for Biomedical Research</a>, Section 13.6.</div><div><br /></div><div>Clinical practice provides anecdotal evidence that biases clinicians. What a clinician sees in her practice is patient i on treatment A and patient j on treatment B. She may remember how patient i fared in comparison to patient j, not appreciate confounding by indication, and suppose this provides a valid estimate of the difference in effectiveness in treatment A vs. B. But the real therapeutic question is how does the outcome of a patient were she given treatment A compare to her outcome were she given treatment B. The gold standard design is thus the randomized crossover design, when the treatment is short acting. Stephen Senn eloquently <a href="http://onlinelibrary.wiley.com/doi/10.1002/sim.6739/abstract">writes</a> about how a 6-period 2-treatment crossover study can even do what proponents of personalized medicine mistakenly think they can do with a parallel-group randomized trial: estimate treatment effectiveness for individual patients.<br /><br />For clinical practice to provide the evidence really needed, the clinician would have to see patients and assign treatments using one of the top four approaches listed in the hierarchy of evidence below. Entries are in the order of strongest evidence requiring the least assumptions to the weakest evidence. Note that crossover studies, when feasible, even surpass randomized studies of matched identical twins in the quality and relevance of information they provide.<br /><br /><span style="font-size: medium;">Let </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;"><span style="font-style: italic;">i</span></span></sub><span style="font-size: medium;"> denote patient </span><span style="font-size: medium;"><span style="font-style: italic;">i</span></span><span style="font-size: medium;"> and the treatments be denoted by </span><span style="font-size: medium;"><span style="font-style: italic;">A</span></span><span style="font-size: medium;"> and </span><span style="font-size: medium;"><span style="font-style: italic;">B</span></span><span style="font-size: medium;">. Thus </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">2</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">B</span></span></sup><span style="font-size: medium;"> represents patient 2 on treatment </span><span style="font-size: medium;"><span style="font-style: italic;">B</span></span><span style="font-size: medium;">. </span><span style="font-size: medium;"><span style="text-decoration: overline;"><span style="font-style: italic;">P</span></span></span><sub><span style="font-size: medium;">1</span></sub><span style="font-size: medium;"> represents the average outcome over a sample of patients from which patient 1 was selected. HTE is heterogeneity of treatment effect.</span><br /><span style="font-size: medium;"><br /></span><br /><table class="cellpading0" style="border-spacing: 6px;"><tbody><tr><td style="white-space: nowrap;"><span style="font-size: large;"><span style="font-weight: bold;">Design</span></span></td><td style="white-space: nowrap;"><span style="font-size: large;"><span style="font-weight: bold;">Patients Compared</span></span><span style="font-size: large;"></span></td></tr><tr><td class="hbar" colspan="2"><span style="font-size: medium;"></span></td></tr><tr><td style="white-space: nowrap;"><span style="font-size: medium;">6-period crossover</span></td><td style="white-space: nowrap;"><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">A</span></span></sup><span style="font-size: medium;"> vs </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">B</span></span></sup><span style="font-size: medium;"> (directly measure HTE)</span></td></tr><tr><td style="white-space: nowrap;"><span style="font-size: medium;">2-period crossover</span></td><td style="white-space: nowrap;"><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">A</span></span></sup><span style="font-size: medium;"> vs </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">B</span></span></sup><span style="font-size: medium;"></span></td></tr><tr><td style="white-space: nowrap;"><span style="font-size: medium;">RCT in idential twins</span></td><td style="white-space: nowrap;"><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">A</span></span></sup><span style="font-size: medium;"> vs </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">B</span></span></sup><span style="font-size: medium;"></span></td></tr><tr><td style="white-space: nowrap;"><span style="font-size: medium;">∥</span><span style="font-size: medium;"> group RCT</span></td><td style="white-space: nowrap;"><span style="font-size: medium;"><span style="text-decoration: overline;"><span style="font-style: italic;">P</span></span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">A</span></span></sup><span style="font-size: medium;"> vs </span><span style="font-size: medium;"><span style="text-decoration: overline;"><span style="font-style: italic;">P</span></span></span><sub><span style="font-size: medium;">2</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">B</span></span></sup><span style="font-size: medium;">, </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><span style="font-size: medium;">=</span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">2</span></sub><span style="font-size: medium;"> on avg</span></td></tr><tr><td style="white-space: nowrap;"><span style="font-size: medium;">Observational, good artificial control</span></td><td style="white-space: nowrap;"><span style="font-size: medium;"><span style="text-decoration: overline;"><span style="font-style: italic;">P</span></span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">A</span></span></sup><span style="font-size: medium;"> vs </span><span style="font-size: medium;"><span style="text-decoration: overline;"><span style="font-style: italic;">P</span></span></span><sub><span style="font-size: medium;">2</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">B</span></span></sup><span style="font-size: medium;">, </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><span style="font-size: medium;">=</span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">2</span></sub><span style="font-size: medium;"> hopefully on avg</span></td></tr><tr><td style="white-space: nowrap;"><span style="font-size: medium;">Observational, poor artificial control</span></td><td style="white-space: nowrap;"><span style="font-size: medium;"><span style="text-decoration: overline;"><span style="font-style: italic;">P</span></span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">A</span></span></sup><span style="font-size: medium;"> vs </span><span style="font-size: medium;"><span style="text-decoration: overline;"><span style="font-style: italic;">P</span></span></span><sub><span style="font-size: medium;">2</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">B</span></span></sup><span style="font-size: medium;">, </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><span style="font-size: medium;">≠ </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">2</span></sub><span style="font-size: medium;"> on avg</span></td></tr><tr><td style="white-space: nowrap;"><span style="font-size: medium;">Real-world physician practice</span></td><td style="white-space: nowrap;"><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">1</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">A</span></span></sup><span style="font-size: medium;"> vs </span><span style="font-size: medium;"><span style="font-style: italic;">P</span></span><sub><span style="font-size: medium;">2</span></sub><sup><span style="font-size: medium;"><span style="font-style: italic;">B</span></span></sup><span style="font-size: medium;"></span></td></tr><tr><td class="hbar" colspan="2"><span style="font-size: medium;"></span></td></tr></tbody></table></div><div><br /></div><div>The best experimental designs yield the best evidence a clinician needs to answer the "what if" therapeutic question for the one patient in front of her.<br /><br />Much more needs to be said about how to handle treatment adherence and what should be the target adherence in an RCT, but overall it is a good thing that RCTs do not mimic clinical practice. We are entering a new era of pragmatic clinical trials. Pragmatic trials are worthy of in-depth discussion, but it is not a stretch to say that the chief advantage of pragmatic trials is not that they provide results that are more relevant to clinical practice but that they are cheaper and faster than traditional randomized trials.<br /><br /></div><div></div><div><br /></div><div><br /></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com0tag:blogger.com,1999:blog-5376139322696503442.post-86293762733253603672017-01-25T06:16:00.001-06:002017-01-25T06:16:46.539-06:00Clinicians' Misunderstanding of Probabilities Makes Them Like Backwards Probabilities Such As Sensitivity, Specificity, and Type I ErrorImaging watching a baseball game, seeing the batter get a hit, and hearing the announcer say "The chance that the batter is left handed is now 0.2!" No one would care. Baseball fans are interested in the chance that a batter will get a hit conditional on his being right handed (handedness being already known to the fan), the handedness of the pitcher, etc. Unless one is an archaeologist or medical examiner, the interest is in forward probabilities conditional on current and past states. We are interested in the probability of the unknown given the known and the probability of a future event given past and present conditions and events.<br /><br />Clinicians are people trained in the science and practice of medicine, and most of them are very good at it. They are also very good at many aspects of research. But they are generally not taught probability, and this can limit their research skills. Many excellent clinicians even let their limitations in understanding probability make them believe that their clinical decision making is worse than it actually is. I have taught many clinicians who say "I need a hard and fast rule so I know how to diagnosis or treat patients. I need a hard cutoff on blood pressure, HbA1c, etc. so that I know what to do, and the fact that I either treat or not treat the patient means that I don't want to consider a probability of disease but desire a simple classification rule." This makes the clinician try to influence the statistician to use inefficient, arbitrary methods such as categorization, stratification, and matching.<br /><br />In reality, clinicians do not act that way when treating patients. They are smart enough to know that if a patient has cholesterol just over someone's arbitrary threshold they may not start statin therapy right away if the patient has no other risk factors (e.g., smoking) going against him. They know that sometimes you start a patient on a lower dose and see how she responds, or start one drug and try it for a while and then switch drugs if the efficacy is unacceptable or there is a significant side effect.<br /><br />So I emphasize the need to understand probabilities when I'm teaching clinicians. A probability is a self-contained summary of the current information, except for the patient's risk aversion and other utilities. Clinicians need to be comfortable with a probability of 0.5 meaning "we don't know much" and not requesting a classification of disease/normal that does nothing but cover up the problem. A classification does not account for gray zones or patient and physician utility functions.<br /><br />Even physicians who understand the meaning of a probability are often not understanding conditioning. Conditioning is all important, and conditioning on different things massively changes the meaning of the probabilities being computed. Every physician I've known has been taught probabilistic medical diagnosis by first learning about sensitivity (sens) and specificity (spec). These are probabilities that are in backwards time- and information flow order. How did this happen? Sensitivity, specificity, and receiver operating characteristic curves were developed for radar and radio research in the military. It was a important to receive radio signals from distant aircraft, and to detect an incoming aircraft on radar. The ability to detect something that is really there is definitely important. In the 1950s, virologists appropriated these concepts to measure the performance of viral cultures. Virus needs to be detected when it's present, and not detected when it's not. Sensitivity is the probability of detecting a condition when it is truly present, and specificity is the probability of not detecting it when it is truly absent. One can see how these probabilities would be useful outside of virology and bacteriology when the samples are retrospective, as in a case-control studies. But I believe that clinicians and researchers would be better off if backward probabilities were not taught or were mentioned only to illustrate how <b>not</b> to think about a problem.<br /><br />But the way medical students are educated, they assume that sens and spec are what you first consider in a prospective cohort of patients! This gives the professor the opportunity of teaching Bayes' rule and requires the use of a supposedly unconditional probability known as <i>prevalence</i> which is actually not very well defined. The students plugs everything into Bayes' rule and fails to notice that several quantities cancel out. The result is the following: the proportion of patients with a positive test who have disease, and the proportion with a negative test who have disease. These are trivially calculated from the cohort data without knowing anything about sens, spec, and Bayes. This way of thinking harms the student's understanding for years to come and influences those who later engage in clinical and pharmaceutical research to believe that type I error and p-values are directly useful.<br /><br />The situation in medical diagnosis gets worse when referral bias (also called workup bias) is present. When certain types of patients do not get a final diagnosis, sens and spec are biased. For example, younger women with a negative test may not get the painful procedure that yields the final diagnosis. There are formulas that must be used to correct sens and spec. But wait! When Bayes' rule is used to obtain the probability of disease we needed in the first place, these corrections completely cancel out when the usual correction methods are used! Using forward probabilities in the first place means that one just conditions on age, sex, and result of the initial diagnostic test and no special methods other than (sometimes) logistic regression are required.<br /><br />There is an analogy to statistical testing. p-values and type I error are affected by sequential testing and a host of other factors, but forward-time probabilities (Bayesian posterior probabilities) are not. Posterior probabilities condition on what is known and does not have to imagine alternate paths to getting to what is known (as do sens and spec when workup bias exists). p-values and type I errors are backwards-information-flow measures, and clinical researchers and regulators come to believe that type I error is the error of interest. They also very frequently misinterpret p-values. The p-value is one minus spec, and power is sens. The posterior probability is exactly analogous to the probability of disease.<br /><br />Sens and spec are so pervasive in medicine, bioinformatics, and biomarker research that we don't question how silly they would be in other contexts. Do we dichotomize a response variable so that we can compute the probability that a patient is on treatment B given a "positive" response? On the contrary we want to know the full continuous distribution of the response given the assigned treatment. Again this represents forward probabilities.<br /><br />Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com10tag:blogger.com,1999:blog-5376139322696503442.post-71852801308958021812017-01-23T07:47:00.002-06:002017-01-25T12:18:25.892-06:00Split-Sample Model ValidationMethods used to obtain unbiased estimates of future performance of statistical prediction models and classifiers include data splitting and resampling. The two most commonly used resampling methods are cross-validation and bootstrapping. To be as good as the bootstrap, about 100 repeats of 10-fold cross-validation are required.<br /><br />As discussed in more detail in Section 5.3 of <a href="http://biostat.mc.vanderbilt.edu/rms">Regression Modeling Strategies Course Notes</a> and the same section of the RMS book, data splitting is an unstable method for validating models or classifiers, especially when the number of subjects is less than about 20,000 (fewer if signal:noise ratio is high). This is because were you to split the data again, develop a new model on the training sample, and test it on the holdout sample, the results are likely to vary significantly. Data splitting requires a significantly larger sample size than resampling to work acceptably well. See also Section 10.11 of <a href="http://biostat.mc.vanderbilt.edu/tmp/bbr.pdf">BBR</a>.<br /><br />There are also very subtle problems:<br /><br /><ol><li>When feature selection is done, data splitting validates just one of a myriad of potential models. In effect it validates an example model. Resampling (repeated cross-validation or the bootstrap) validate the process that was used to develop the model. Resampling is honest in reporting the results because it depicts the uncertainty in feature selection, e.g., the disagreements in which variables are selected from one resample to the next.</li><li>It is not uncommon for researchers to be disappointed in the test sample validation and to ask for a "re-do" whereby another split is made or the modeling starts over, or both. When reporting the final result they sometimes neglect to mention that the result was the third attempt at validation.</li><li>Users of split-sample validation are wise to recombine the two samples to get a better model once the first model is validated. But then they have no validation of the new combined data model.</li></ol><div>There is a less subtle problem but one that is ordinarily not addressed by investigators: unless both the training and test samples are huge, split-sample validation is not nearly as accurate as the bootstrap. See for example the section <i>Studies of Methods Used in the Text </i><a href="http://biostat.mc.vanderbilt.edu/rms">here</a>. As shown in a simulation appearing there, bootstrapping is typically more accurate than data splitting and cross-validation that does not use a large number of repeats. This is shown by estimating the "true" performance, e.g., the R-squared or c-index on an infinitely large dataset (infinite here means 50,000 subjects for practical purposes). The performance of an accuracy estimate is taken as the mean squared error of the estimate against the model's performance in the 50,000 subjects.</div><div><br /></div><div>Data are too precious to not be used in model development/parameter estimation. Resampling methods allow the data to be used for both development and validation, and they do a good job in estimating the likely future performance of a model. Data splitting only has an advantage when the test sample is held by another researcher to ensure that the validation is unbiased.<br /><br /><h3>Update 2017-01-25</h3>Many investigators have been told that they must do an "external" validation, and they split the data by time or geographical location. They are sometimes surprised that the model developed in one country or time does not validate in another. They should not be; this is an indirect way of saying there are time or country effects. Far better would be to learn about and estimate time and location effects by including them in a unified model. Then rigorous internal validation using the bootstrap, accounting for time and location all along the way. The end result is a model that is useful for prediction at times and locations that were at least somewhat represented in the original dataset, but without assuming that time and location effects are nil.<br /><br /></div><div><br /></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com6tag:blogger.com,1999:blog-5376139322696503442.post-9469918730797607892017-01-18T18:33:00.000-06:002017-03-04T12:17:07.654-06:00Fundamental Principles of StatisticsThere are many principles involved in the theory and practice of statistics, but here are the ones that guide my practice the most.<br /><ol><li>Use methods grounded in theory or extensive simulation</li><li>Understand uncertainty</li><li>Design experiments to maximize information</li><li>Understand the measurements you are analyzing and don't hesitate to question how the underlying information was captured</li><li>Be more interested in questions than in null hypotheses, and be more interested in estimation than in answering narrow questions</li><li>Use all information in data during analysis</li><li>Use discovery and estimation procedures not likely to claim that noise is signal</li><li>Strive for optimal quantification of evidence about effects</li><li>Give decision makers the inputs (<i>other</i> than the utility function) that optimize decisions</li><li>Present information in ways that are intuitive, maximize information content, and are correctly perceived</li><li>Give the client what she needs, not what she wants</li><li>Teach the client to want what she needs</li></ol><div><i><span style="font-size: x-small;"><br /></span></i><i><span style="font-size: x-small;">... the statistician must be instinctively and primarily a logician and a scientist in the broader sense, and only secondarily a user of the specialized statistical techniques.</span></i><br /><i><span style="font-size: x-small;"><br /></span></i><i><span style="font-size: x-small;">In considering the refinements and modifications of the scientific method which particularly apply to the work of the statistician, the first point to be emphasized is that the statistician is always dealing with probabilities and degrees of uncertainty. He is, in effect, a Sherlock Holmes of figures, who must work mainly, or wholly, from circumstantial evidence.</span></i><br /><br /><div style="text-align: right;"><span style="font-size: x-small;">Malcolm C Rorty: Statistics and the Scientific Method. JASA 26:1-10, 1931.</span></div></div><div><span style="font-size: x-small;"><br /></span></div><br /><div><br /></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com0tag:blogger.com,1999:blog-5376139322696503442.post-12827695989229990502017-01-16T10:52:00.002-06:002017-01-24T07:28:15.871-06:00Ideas for Future Articles<div class="MsoNormal" style="background-color: white; margin: 0cm 0cm 10pt;"></div><div>Suggestions for future articles are welcomed as comments to this entry. Some topics I intend to write about are listed below.</div><ol><li><span style="color: #222222; font-family: "calibri";">The litany of problems with p-values - catalog of all the problems I can think of</span></li><li><span style="color: #222222; font-family: "calibri";">Matching vs. covariate adjustment (see below from Arne Warnke)</span></li><li><span style="color: #222222; font-family: "calibri";">Statistical strategy for propensity score modeling and usage</span></li><li><span style="color: #222222; font-family: "calibri";">Analysis of change: why so many things go wrong</span></li><li><span style="color: #222222; font-family: "calibri";">What exactly is a type I error and should we care? (analogy: worrying about the chance of a false positive diagnostic test vs. computing current probability of disease given whatever the test result was). Alternate title: Why Clinicians' Misunderstanding of Probabilities Makes Them Like Backwards Probabilities Such As Sensitivity, Specificity, and Type I Error.</span></li><li><span style="color: #222222; font-family: "calibri";">Forward vs. backwards probabilities and why forward probabilities serve as their own error probabilities (we have been fed backwards probabilities such as p-values, sensitivity, and specificity for so long it's hard to look forward)</span></li><li><span style="color: #222222; font-family: "calibri";">What is the full meaning of a posterior probability?</span></li><li><span style="color: #222222; font-family: "calibri";">Posterior probabilities can be computed as often as desired</span></li><li><span style="color: #222222; font-family: "calibri";">Statistical critiques of published articles in the biomedical literature</span></li><li><span style="color: #222222; font-family: "calibri";">New dynamic graphics capabilities using R plotly in the R Hmisc package: Showing more by initially showing less</span></li><li><span style="color: #222222; font-family: "calibri";">Moving from pdf to html for statistical reporting</span></li><li><span style="color: #222222; font-family: "calibri";">Is machine learning statistics or computer science?</span></li><li><span style="color: #222222; font-family: "calibri";">Sample size calculation: Is it voodoo?</span></li><li><span style="color: #222222; font-family: "calibri";">Difference between Bayesian modeling and frequentist inference</span></li><li><span style="color: #222222; font-family: "calibri";">Proper accuracy scoring rules and why improper scores such as proportion "classified" "correctly" give misleading results.</span></li></ol><br /><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span style="font-size: small;"><span style="font-family: "calibri";"></span></span></div><a name='more'></a><span style="font-size: small;"><span style="font-family: "calibri";"><br /></span></span><br /><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span style="font-size: small;"><span style="font-family: "calibri";">A few weeks ago we had a small discussion at CrossValidated about the pros and cons of matching.<u></u><u></u></span></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span style="font-size: small;"><span style="font-family: "calibri";"><a data-saferedirecturl="https://www.google.com/url?hl=en&q=http://stats.stackexchange.com/questions/248676/analysis-strategy-for-rare-outcome-with-matching&source=gmail&ust=1484667382479000&usg=AFQjCNGeqIzlveltVWYDrMAJ7NOTMDrWjw" href="http://stats.stackexchange.com/questions/248676/analysis-strategy-for-rare-outcome-with-matching" style="color: #1155cc;" target="_blank">http://stats.stackexchange.<wbr></wbr>com/questions/248676/analysis-<wbr></wbr>strategy-for-rare-outcome-<wbr></wbr>with-matching</a></span></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span style="font-size: small;"><span style="font-family: "calibri";">I am sorry that I did not had enough time to elaborate further on the support of matching procedures (in my field researchers do not focus much on a bias-variance tradeoff but they prioritize on minimizing biases. For that reason, they like matching procedures).<u></u><u></u></span></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span style="font-family: "calibri";"><span style="font-size: small;">Now, I have seen that you started a blog recently (congratulations!). </span></span><span style="font-family: "calibri";"><span style="font-size: small;">I would like to encourage to take up the topic of matching because it is probably interesting for many applied researchers.<br />I think in your ‘philosophy’, this would belong to the point “Preserve all the information in the data”.<u></u><u></u></span></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span style="font-size: small;"><span style="font-family: "calibri";">Here, perhaps some input for a blog post. Back then, you wrote:<u></u><u></u></span></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span class="m_-6858845881952282685comment-copy"><i><span style="font-size: small;"><span style="font-family: "calibri";">Matching on continuous variables results in an incomplete adjustment because the variables have to be binned.<u></u><u></u></span></span></i></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span class="m_-6858845881952282685comment-copy"><span style="font-size: small;"><span style="font-family: "calibri";">What about propensity score matching?<u></u><u></u></span></span></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span class="m_-6858845881952282685comment-copy"><i><span style="font-size: small;"><span style="font-family: "calibri";">Matching throws away good data from observations that would be good matches.<u></u><u></u></span></span></i></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span class="m_-6858845881952282685comment-copy"><span style="font-size: small;"><span style="font-family: "calibri";">I agree<u></u><u></u></span></span></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span class="m_-6858845881952282685comment-copy"><i><span style="font-size: small;"><span style="font-family: "calibri";">Extrapolation bias is only a significant problem if there is a covariate by group interaction, and users of matching methods ignore interactions anyway.<u></u><u></u></span></span></i></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span class="m_-6858845881952282685comment-copy"><span style="font-size: small;"><span style="font-family: "calibri";">Here, you go too far (in my view). You can add interactions, again for example with propensity score matching. Imbens and Rubin (2015) suggest a procedure using quadratic and interaction terms of the covariates.<u></u><u></u></span></span></span><br /><br /> Comment: Nice to know this exists but I've never seen a paper that used matching attempt to explore interactions.</div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span style="font-size: small;"><span style="font-family: "calibri";"><span class="m_-6858845881952282685comment-copy"><i>If you don't want to make regression assumptions that are unverifiable, remove observations outside the overlap region just as with matching.</i></span><i><u></u><u></u></i></span></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "segoe ui"; margin: 0cm 0cm 10pt;"><div style="font-size: 13.3333px;"><span style="font-size: small;"><span style="font-family: "calibri";">Which assumptions do you refer to? I think that treating everyone the same (statistically) is also an unverifiable assumption (do you disagree?). What is your opinion about weighted least squares?<u></u><u></u></span></span></div><div style="font-size: 13.3333px;"><span style="font-size: small;"><span style="font-family: "calibri";"><br /></span></span></div><span style="font-size: x-small;"><span style="font-family: "calibri";"><span style="font-size: 13.3333px;"> </span><span style="font-size: x-small;">Comment: This is the no-interaction assumption. If you assume additivity then it's more OK to have a no-overlap region, otherwise throw-away non-overlap regions and do a conditional analysis. Not clear on the need for weighting here. In general I like conditioning over weighting.</span></span></span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span style="font-family: "calibri"; font-size: small;">Arne Jonas Warnke</span></div><div class="MsoNormal" style="background-color: white; color: #222222; font-family: "Segoe UI"; font-size: 13.3333px; margin: 0cm 0cm 10pt;"><span style="font-family: "calibri"; font-size: small;">Labour Markets, Human Resources and Social Policy<br />Internet: <a data-saferedirecturl="https://www.google.com/url?hl=en&q=http://www.zew.de&source=gmail&ust=1484667382500000&usg=AFQjCNEWgTCixFOJMtuAG_jF2Z6OHrpGmA" href="http://www.zew.de/" style="color: #1155cc;" target="_blank">www.zew.de</a> <a data-saferedirecturl="https://www.google.com/url?hl=en&q=http://www.zew.eu&source=gmail&ust=1484667382500000&usg=AFQjCNGpB0ievH9X1dB4ZfmY9XFeqhsA-A" href="http://www.zew.eu/" style="color: #1155cc;" target="_blank">www.zew.eu</a></span></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com37tag:blogger.com,1999:blog-5376139322696503442.post-40024397928327588772017-01-15T11:51:00.002-06:002017-01-15T12:31:59.739-06:00Classification vs. PredictionThe field of machine learning arose somewhat independently of the field of statistics. As a result, machine learning experts tend not to emphasize probabilistic thinking. Probabilistic thinking and understanding uncertainty and variation are hallmarks of statistics. By the way, one of the best books about probabilistic thinking is Nate Silver's <i>The Signal and The Noise: Why So Many Predictions Fail But Some Don't</i>. In the medical field, a classic paper is David Spiegelhalter's <a href="http://www.citeulike.org/user/harrelfe/article/13264888">Probabilistic Prediction in Patient Management and Clinical Trials</a>.<br /><br />By not thinking probabilistically, machine learning advocates frequently utilize classifiers instead of using risk prediction models. The situation has gotten acute: many machine learning experts actually label logistic regression as a classification method (it is not). It is important to think about what classification really implies. Classification is in effect a decision. Optimum decisions require making full use of available data, developing predictions, and applying a loss/utility/cost function to make a decision that, for example, minimizes expected loss or maximizes expected utility. Different end users have different utility functions. In risk assessment this leads to their having different risk thresholds for action. Classification assumes that every user has the same utility function and that the utility function implied by the classification system is<i> that</i> utility function.<br /><br />Classification is a <i>forced choice</i>. In marketing where the advertising budget is fixed, analysts generally know better than to try to classify a potential customer as someone to ignore or someone to spend resources on. They do this by modeling probabilities and creating a <i>lift curve</i>, whereby potential customers are sorted in decreasing order of estimated probability of purchasing a product. To get the "biggest bang for the buck", the marketer who can afford to advertise to n persons picks the n highest-probability customers as targets. This is rational, and classification is not needed here.<br /><br />A frequent argument from data users, e.g., physicians, is that ultimately they need to make a binary decision, so binary classification is needed. This is simply not true. First of all, it is often the case that the best decision is "no decision; get more data" when the probability of disease is in the middle. In many other cases, the decision is revocable, e.g., the physician starts the patient on a drug at a lower dose and decides later whether to change the dose or the medication. In surgical therapy the decision to operate is irrevocable, but the choice of <i>when</i> to operate is up to the surgeon and the patient and depends on severity of disease and symptoms. At any rate, if binary classification is needed, it must be done <b>at the point of care when all utilities are known</b>, not in a data analysis.<br /><br />When are forced choices appropriate? I think that one needs to consider whether the problem is mechanistic or stochastic/probabilistic. Machine learning advocates often want to apply methods made for the former to problems where biologic variation, sampling variability, and measurement errors exist. It may be best to apply classification techniques instead just to high signal:noise ratio situations such as those in which there there is a known gold standard and one can replicate the experiment and get almost the same result each time. An example is pattern recognition - visual, sound, chemical composition, etc. If one creates an optical character recognition algorithm, the algorithm can be trained by exposing it to any number of replicates of attempts to classify an image as the letters A, B, ... The user of such a classifier may not have time to consider whether any of the classifications were "close calls." And the signal:noise ratio is extremely high.<br /><br />When close calls are possible, probability estimates are called for. One beauty of probabilities is that they are their own error measures. If the probability of disease is 0.1 and the current decision is not to treat the patient, the probability of this being an error is by definition 0.1. A probability of 0.4 may lead the physician to run another lab test or do a biopsy.<br /><br />The U.S. Weather Service has always phrased rain forecasts as probabilities. I do not want a classification of "it will rain today." There is a slight loss/disutility of carrying an umbrella, and I want to be the one to make the tradeoff.<br /><br />Whether engaging in credit risk scoring, weather forecasting, climate forecasting, marketing, diagnosis a patient's disease, or estimating a patient's prognosis, I do not want to use a classification method. I want risk estimates with credible intervals or confidence intervals. My opinion is that machine learning classifiers are best used in mechanistic high signal:noise ratio situations, and that probability models should be used in most other situations.<br /><br />This is related to a subtle point that has been lost on many analysts. Complex machine learning algorithms, which allow for complexities such as high-order interactions, require an <a href="http://www.citeulike.org/user/harrelfe/article/13467382">enormous amount of data</a> unless the signal:noise ratio is high, another reason for reserving some machine learning techniques for such situations. Regression models which capitalize on additivity assumptions (when they are true, and this is approximately true is much of the time) can yield accurate probability models without having massive datasets. And when the outcome variable being predicted has more than two levels, a single regression model fit can be used to obtain all kinds of interesting quantities, e.g., predicted mean, quantiles, exceedance probabilities, and instantaneous hazard rates.<br /><br />A special problem with classifiers illustrates an important issue. Users of machine classifiers know that a highly imbalanced sample with regard to a binary outcome variable Y results in a strange classifier. For example, if the sample has 1000 diseased patients and 1,000,000 non-diseased patients, the best classifier may classify everyone as non-diseased; you will be correct 0.999 of the time. For this reason the odd practice of subsampling the controls is used in an attempt to balance the frequencies and get some variation that will lead to sensible looking classifiers (users of regression models would never exclude good data to get an answer). Then they have to, in some ill-defined way, construct the classifier to make up for biasing the sample. It is simply the case that a classifier trained to a 1/1000 prevalence situation will not be applicable to a population with a vastly different prevalence. The classifier would have to be re-trained on the new sample, and the patterns detected may change greatly. Logistic regression on the other hand elegantly handles this situation by either (1) having as predictors the variables that made the prevalence so low, or (2) recalibrating the intercept (only) for another dataset with much higher prevalence. Classifiers' extreme dependence on prevalence may be enough to make some researchers always use probability estimators instead.<br /><br />One of the key elements in choosing a method is having a sensitive accuracy scoring rule with the correct statistical properties. Experts in machine classification seldom have the background to understand this enormously important issue, and choosing an improper accuracy score such as proportion classified correctly will result in a bogus model. This will be discussed in a future blog.<br /><br />Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com19tag:blogger.com,1999:blog-5376139322696503442.post-56405130006316528232017-01-14T08:14:00.001-06:002017-01-26T22:30:54.497-06:00p-values and Type I Errors are Not the Probabilities We NeedIn trying to guard against false conclusions, researchers often attempt to minimize the risk of a "false positive" conclusion. In the field of assessing the efficacy of medical and behavioral treatments for improving subjects' outcomes, falsely concluding that a treatment is effective when it is not is an important consideration. Nowhere is this more important than in the drug and medical device regulatory environments, because a treatment thought not to work can be given a second chance as better data arrive, but a treatment judged to be effective may be approved for marketing, and if later data show that the treatment was actually not effective (or was only trivially effective) it is difficult to remove the treatment from the market if it is safe. The probability of a treatment not being effective is the probability of "regulator's regret." One must be very clear on what is conditioned upon (assumed) in computing this probability. Does one condition on the true effectiveness or does one condition on the available data? Type I error conditions on the treatment having no effect and does not entertain the possibility that the treatment actually worsens the patients' outcomes. Can one quantify evidence for making a wrong decision if one assumes that all conclusions of non-zero effect are wrong up front because H<sub>0</sub> was assumed to be true? Aren't useful error probabilities the ones that are not based on assumptions about what we are assessing but rather just on the data available to us?<br /><br />Statisticians have convinced regulators that long-run operating characteristics of a testing procedure should rule the day, e.g., if we did 1000 clinical trials where efficacy was always zero, we want no more than 50 of these trials to be judged as "positive." Never mind that this type I error operating characteristic does not refer to making a correct judgment for the clinical trial at hand. Still, there is a belief that type I error is the probability of regulator's regret (a false positive), i.e., that the treatment is not effective when the data indicate it is. In fact, clinical trialists have been sold a bill of goods by statisticians. No probability derived from an assumption that the treatment has zero effect can provide evidence about that effect. Nor does it measure the chance of the error actually in question. All probabilities are conditional on <i>something</i>, and to be useful they must condition on the <i>right thing</i>. This usually means that what is conditioned upon must be knowable.<br /><br />The probability of regulator's regret is the probability that a treatment doesn't work given the data. So the probability we really seek is the probability that the treatment has no effect <i>or that it has a backwards effect</i>. This is precisely one minus the Bayesian posterior probability of efficacy.<br /><br />In reality, there is unlikely to exist a treatment that has exactly zero effect. As <a href="http://www.citeulike.org/user/harrelfe/article/10529649">Tukey argued in 1991</a>, the effects of treatments A and B are always different, to some decimal place. So the null hypothesis is always false and the type I error could be said to be always zero.<br /><br />The best paper I've read about the many ways in which p-values are misinterpreted is <a href="http://www.citeulike.org/user/harrelfe/article/14042559">Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations</a> written by a group of renowned statisticians. One of my favorite quotes from this paper is<br /><br /><blockquote class="tr_bq">Thus to claim that the null P value is the probability that chance alone produced the observed association is completely backwards: The P value is a probability computed assuming chance was operating alone. The absurdity of the common backwards interpretation might be appreciated by pondering how the P value, which is a probability deduced from a set of assumptions (the statistical model), can possibly refer to the probability of those assumptions.</blockquote>In 2016 the American Statistical Association took a <a href="https://matloff.wordpress.com/2016/03/07/after-150-years-the-asa-says-no-to-p-values">stand</a> against over-reliance on p-values. This would have made a massive impact on all branches of science had it been issued 50 years ago but better late than never.<br /><br /><h3>Update 2017-01-19</h3>Though believed to be true by many non-statisticians, p-values are not the probability that H<sub>0</sub> is true, and to turn them into such probabilities requires Bayes' rule. If you are going to use Bayes' rule you might as well formulate the problem as a full Bayesian model. This has many benefits, not the least of them being that you can select an appropriate prior distribution and you will get exact inference. Attempts by several authors to convert p-values to probabilities of interest (just as sensitivity and specificity are converted to probability of disease once one knows the prevalence of disease) have taken the prior to be discontinuous, putting a high probability on H<sub>0</sub> being exactly true. In my view it is much more sensible to believe that there is no discontinuity in the prior at the point represented by H<sub>0</sub>, encapsulating prior knowledge instead by saying that values near H<sub>0</sub> are more likely if no relevant prior information is available.<br /><br />Returning to the non-relevance of type I error as discussed above, and ignoring for the moment that long-run operating characteristics do not directly assist us in making judgments about the current experiment, there is a subtle problem that leads researchers to believe that by controlling type I "error" they think they have quantified the probability of misleading evidence. As discussed at length by my colleague <a href="http://www.citeulike.org/user/harrelfe/author/Blume">Jeffrey Blume</a>, once an experiment is done the probability that positive evidence is misleading is <b>not</b> type I error. And what exactly does "error" mean in "type I error?" It is the probability of rejecting H<sub>0</sub> when H<sub>0</sub> is exactly true, just as the p-value is the probability of obtaining data more impressive than that observed given H<sub>0</sub> is true. Are these really error probabilities? Perhaps ... if you have been misled earlier into believing that we should base conclusions on how unlikely the observed data would have been observed under H<sub>0</sub>. Part of the problem is in the loaded word "reject." Rejecting H<sub>0</sub> by seeing data that are unlikely if H<sub>0</sub> is true is perhaps the real error.<br /><br />The "error quantification" truly needed is the probability that a treatment doesn't work given all the current evidence, which as stated above is simply one minus the Bayesian posterior probability of positive efficacy.<br /><br /><h3>Update 2017-01-20</h3>Type I error control is an indirect way to being careful about claims of effects. It should never have been the preferred method for achieving that goal. Seen another way, we would choose type I error as the quantity to be controlled if we wanted to:<br /><br /><ul><li>require the experimenter to visualize an infinite number of experiments that might have been run, and assume that the current experiment could be exactly replicated</li><li>be interested in long-run operating characteristics vs. judgments needing to be made for the one experiment at hand</li><li>be interested in the probability that other replications result in data more extreme than mine if there is no treatment effect</li><li>require early looks at the data to be discounted for future looks</li><li>require past looks at the data to be discounted for earlier inconsequential looks</li><li>create other multiplicity considerations, all of them arising from the chances you give data to be extreme as opposed to the chances that you give effects to be positive</li><li>data can be more extreme for a variety of reasons such as trying to learn faster by looking more often or trying to learn more by comparing more doses or more drugs</li></ul><div>The Bayesian approach focuses on the chances you give effects to be positive and does not have multiplicity issues (potential issues such as examining treatment effects in multiple subgroups are handled by the shrinkage that automatically results when you use the 'right' Bayesian hierarchical model).</div><div><br /></div><div>The p-value is the chance that someone else would observe data more extreme than mine (if they could exactly replicate my experiment) and not the probability of no (or a negative) effect of treatment given my data.</div><div><br /></div><br /><br />Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com9tag:blogger.com,1999:blog-5376139322696503442.post-58513343866216728782017-01-14T07:15:00.001-06:002017-01-15T20:25:45.952-06:00Null Hypothesis Significance Testing Never WorkedMuch has been written about problems with our most-used statistical paradigm: frequentist null hypothesis significance testing (NHST), p-values, type I and type II errors, and confidence intervals. Rejection of straw-man null hypotheses leads researchers to believe that their theories are supported, and the unquestioning use of a threshold such as p<0.05 has resulted in hypothesis substitution, search for subgroups, and other gaming that has badly damaged science. But we seldom examine whether the original idea of NHST actually delivered on its goal of making good decisions about effects, given the data.<br /><br />NHST is based on something akin to proof by contradiction. The best non-mathematical definition of the p-value I've ever seen is due to <a href="http://www.citeulike.org/user/harrelfe/article/14166520">Nicholas Maxwell</a>: "the degree to which the data are embarrassed by the null hypothesis." p-values provide evidence against something, never in favor of something, and are the basis for NHST. But proof by contradiction is only fully valid in the context of rules of logic where assertions are true or false without any uncertainty. The classic paper <a href="http://www.citeulike.org/user/harrelfe/article/10529649">The Earth is Round (p<.05)</a> by Jacob Cohen has a beautiful example pointing out the fallacy of combining probabilistic ideas with proof by contradiction in an attempt to make decisions about an effect.<br /><blockquote class="tr_bq"><br />The following is almost but not quite the reasononing of null hypothesis rejection: </blockquote><blockquote class="tr_bq">If the null hypothesis is correct, then this datum (D) can not occur.<br />It has, however, occurred.<br />Therefore the null hypothesis is false. </blockquote><blockquote class="tr_bq">If this were the reasoning of H<sub>0</sub> testing, then it would be formally correct. … But this is not the reasoning of NHST. Instead, it makes this reasoning probabilistic, as follows: </blockquote><blockquote class="tr_bq">If the null hypothesis is correct, then these data are highly unlikely.<br />These data have occurred.<br />Therefore, the null hypothesis is highly unlikely. </blockquote><blockquote class="tr_bq">By making it probabilistic, it becomes invalid. … the syllogism becomes formally incorrect and leads to a conclusion that is not sensible: </blockquote><blockquote class="tr_bq">If a person is an American, then he is probably not a member of Congress. (TRUE, RIGHT?)<br />This person is a member of Congress.<br />Therefore, he is probably not an American. (Pollard & Richardson, 1987) </blockquote><blockquote class="tr_bq">… The illusion of attaining improbability or the Bayesian Id's wishful thinking error …<br /> </blockquote><blockquote class="tr_bq">Induction has long been a problem in the philosophy of science. Meehl (1990) attributed to the distinguished philosopher Morris Raphael Cohen the saying "All logic texts are divided into two parts. In the first part, on deductive logic, the fallacies are explained; in the second part, on inductive logic, they are committed."</blockquote>Sometimes when an approach leads to numerous problems, the approach itself is OK and the problems can be repaired. But besides all the other problems caused by NHST (including need for arbitrary multiplicity adjustments, need for consideration of investigator intentions and not just her actions, rejecting H<sub>0</sub> for trivial effects, incentivizing gaming, interpretation difficulties, etc.) it may be the case that the overall approach is defective and should not have been adopted.<br /><br />With all of the amazing things Ronald Fisher gave us, and even though he recommended against the unthinking rejection of H<sub>0</sub>, his frequentist approach and dislike of the Bayesian approach did us all a disservice. He called the Bayesian method invalid and was possibly intellectually dishonest when he labeled it as "inverse probability." In fact the p-value is an indirect inverse probability and Bayesian posterior probabilities are direct forwards probabilities that do not condition on a hypothesis, and the Bayesian approach has not only been shown to be valid, but it actually delivers on its promise.<br /><br />Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com21tag:blogger.com,1999:blog-5376139322696503442.post-75934167279084927472017-01-13T07:49:00.001-06:002017-01-13T13:44:39.262-06:00IntroductionStatistics is a field that is a science unto itself and that benefits all other fields and everyday life. What is unique about statistics is its proven tools for decision making in the face of uncertainty, understanding sources of variation and bias, and most importantly, <i>statistical thinking</i>. Statistical thinking is a different way of thinking that is part detective, skeptical, and involves alternate takes on a problem. An excellent example of statistical thinking is statistician Abraham Wald's <a href="https://en.wikipedia.org/wiki/Abraham_Wald">analysis</a> of British bombers surviving to return to their base in World War II: his conclusion was to reinforce bombers in areas in which no damage was observed. For other great examples watch my colleague Chris Fonnesbeck's <a href="https://www.youtube.com/watch?v=TGGGDpb04Yc">Statistical Thinking for Data Science</a>.<br /><br />Some of my personal philosophy of statistics can be summed up in the list below:<br /><ul style="background-color: white; font-family: arial, verdana, sans-serif; font-size: 14px;"><li style="background-color: transparent;">Statistics needs to be fully integrated into research; experimental design is all important</li><li style="background-color: transparent;">Don't be afraid of using modern methods</li><li style="background-color: transparent;">Preserve all the information in the data; Avoid categorizing continuous variables and predicted values at all costs</li><li style="background-color: transparent;">Don't assume that anything operates linearly</li><li style="background-color: transparent;">Account for model uncertainty and avoid it when possible by using subject matter knowledge</li><li style="background-color: transparent;">Use the bootstrap routinely</li><li style="background-color: transparent;">Make the sample size a random variable when possible</li><li style="background-color: transparent;">Use Bayesian methods whenever possible</li><li style="background-color: transparent;">Use excellent graphics, liberally</li><li style="background-color: transparent;">To be trustworthy research must be reproducible</li><li style="background-color: transparent;">All data manipulation and statistical analysis <b>must</b> be reproducible (one ramification being that I advise against the use of point and click software in most cases)</li></ul><div><span style="font-family: "arial" , "verdana" , sans-serif;"><span style="font-size: 14px;">Statistics has multiple challenges today, which I break down into three major sources:</span></span></div><div><ol><li><span style="font-family: "arial" , "verdana" , sans-serif;"><span style="font-size: 14px;">Statistics has been and continues to be taught in a traditional way, leading to statisticians believing that our historical approach to estimation, prediction, and inference was good enough.</span></span></li><li><span style="font-family: "arial" , "verdana" , sans-serif;"><span style="font-size: 14px;">Statisticians do not receive sufficient training in computer science and computational methods, too often leaving those areas to others who get so good at dealing with vast quantities of data that they assume they can be self-sufficient in statistical analysis and not seek involvement of statisticians. Many persons who analyze data do not have sufficient training in statistics.</span></span></li><li><span style="font-family: "arial" , "verdana" , sans-serif;"><span style="font-size: 14px;">Subject matter experts (e.g., clinical researchers and epidemiologists) try to avoid statistical complexity by "dumbing down" the problem using dichotomization, and statisticians, always trying to be helpful, fail to argue the case that dichotomization of continuous or ordinal variables is almost never an appropriate way to view or analyze data. Statisticians in general do not sufficiently involve themselves in measurement issues.</span></span></li></ol><div><span style="font-family: "arial" , "verdana" , sans-serif;"><span style="font-size: 14px;">I will be discussing several of the issues in future blogs, especially item 1 above and items 2 and 4 below.</span></span><br /><span style="font-family: "arial" , "verdana" , sans-serif;"><span style="font-size: 14px;"><br /></span></span><span style="font-family: "arial" , "verdana" , sans-serif;"><span style="font-size: 14px;">Complacency in the field of statistics and in statistical education has resulted in </span></span></div><div><ol><li>reliance on large-sample theory so that inaccurate normal distribution-based tools can be used, as opposed to tailoring the analyses to data characteristics using the bootstrap and semiparametric models</li><li>belief that null hypothesis significance testing ever answered the scientific question and the p-values are useful</li><li>avoidance of the likelihood school of inference (relative likelihood, likelihood support intervals, likelihood ratios, etc.)</li><li>avoidance of Bayesian methods (posterior distributions, credible intervals, predictive distributions, etc.)</li></ol><div><br /></div></div></div><div><br /></div>Frank Harrellhttp://www.blogger.com/profile/15263496257600444093noreply@blogger.com4