**[The Monthly Mean] May/June 2010--The FTC calls me about small sample size
issues**

Welcome to the Monthly Mean newsletter for May 2010. If you are having trouble reading this newsletter in your email system, please go to www.pmean.com/news/201005.html. If you are not yet subscribed to this newsletter, you can sign on at www.pmean.com/news. If you no longer wish to receive this newsletter, there is a link to unsubscribe at the bottom of this email. Here's a list of topics.

Lead article: The FTC calls me about small sample size issues

2. Positive and negative predictive values

3. Understanding the interaction of two continuous variables

4. Monthly Mean Article (peer reviewed): Overdiagnosis in Cancer

5. Monthly Mean Article (popular press): The Data-Driven Life

6. Monthly Mean Book: Voodoo Histories

7. Monthly Mean Definition: What is socioeconomic status

8. Monthly Mean Quote:When we meet a fact...

9. Monthly Mean Unsung Hero Award: Martin Holt

10. Monthly Mean Website: Centre for Multilevel Modelling (CMM)

11. Nick News: Nicholas buys and builds his own basketball hoop

12. Very bad joke:Three people are brought in...

13. Tell me what you think.

14. Upcoming statistics webinars

15. Join me on Facebook and LinkedIn

**1. The FTC calls me about small sample size issues**

I was involved in an interesting court case two years ago, very indirectly, and it raises some important issues about small sample sizes. I didn't want to write about it while it was happening, to avoid problems with violations of confidentiality. With the lapse of time, though, and with careful writing, I hope I won't betray anyone's secrets.

A manufacturer of some sort of nutritional supplement was making an advertising claim based on a paper published in the peer-reviewed literature. The Federal Trade Commission disputed this claim and said it was not supported by this particular study. The study in question was a randomized study, which is pretty good, but the sample size was quite small, around a dozen patients total. The results did achieve statistical significance. That sounds good, statistical significance makes a small sample size choice look not so bad in retrospect. There's another problem, though, with small sample sizes in a randomized study.

Randomization relies on the law of large numbers. Just as ten flips of a coin will not guarantee a perfectly even distribution of heads and tails throughout the sequence, a randomized study of a small number of patients will not guarantee an equal mixture of very sick and mildly ill patients in the treatment and control group. Some degree of covariate imbalance can creep in.

So the question becomes, how large does the sample size need to be in order to insure that chance equalizes out the key covariates. This was studied in

- L M Hsu.
Random sampling, randomization, and equivalence of contrasted groups in psychotherapy outcome research. J Consult Clin Psychol. 1989;57(1):131-7.Abstract: "Random sampling and random assignment (randomization) are some of the most popular methods of equating contrasted groups on pre-existing nuisance variables. However, the small samples typically used in psychotherapy outcome studies raise some questions about the extent to which these methods eliminate the pretreatment nonequivalence of groups in this area of research. This article identifies conditions under which equivalence is likely (and unlikely) to be attained with simple random sampling and randomization in psychotherapy efficacy studies of the kind examined in recent meta-analyses. Some consequences of nonequivalence are viewed as manifestations of Simpson's paradox. Misinterpretations of estimates of the relative efficacy of treatments are expected in view of belief in the law of small numbers. The minimum sample sizes needed to protect against nonequivalence are compared with those needed to satisfy several other criteria."[Accessed February 18, 2009]. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2647799.This paper used simulation to see how often a serious imbalance in covariates would occur in spite of randomization. With a total sample size of 10, there was a 50% probability that a single key categorical covariate would show serious imbalance (twice as many of one category in the treatment group as in the control group). A total sample size of 40, however, would protect against serious imbalance even with two or three key categorical covariates. This is all described in Chapter 1 of my book, Statistical Evidence.

I got a call from a lawyer at the Federal Trade Commission (FTC) who wanted to use my book as an argument that you can't make a claim based on a sample size of a dozen patients, even with randomization. I don't see the world as starkly as that. A small sample size is a problem because of what Hsu has shown, but it is just one of many factors that need to be considered. I tried to explain this, though I'm not sure how successful I was.

Then I get a call from a lawyer representing the manufacturer. He said that he was worried that the FTC lawyer was twisting my arguments and taking them out of context. So I explained the same thing to this lawyer. I kept on getting phone calls back and forth from the competing lawyers, each trying to get me to testify on their side.

The lawyers for the company did offer to pay me to serve as an "expert witness" on this case, and I saw the cash register ringing in the back of my head. But thankfully, I asked to look at the paper in question first.

A small sample size is not an automatic disqualification, if the other aspects of the research are carefully handled. A weak study can still be persuasive if you can find sufficient corroborating evidence. But this paper had a lot of problems with it, not just the small sample size. So I tried to patiently explain in a conference call what those other problems were. There was nothing at all, in my opinion, for any sort of efficacy claim that this company might try to make. It was a very short phone call.

If I wanted to, I could have billed the company lawyer for my time spent on reviewing the paper, and I'm sure they would have paid. But my heart wasn't in it. I just let the matter drop. I have no idea how the case ended up.

The moral for this is that the adversarial nature of our legal system tends to seek out extreme opinions. A muddler and a middle of the road person like me will never do that well in such a system.

**2. Positive and negative predictive values**

In the February/March 2010 issue of The Monthly Mean, I talked about sensitivity and specificity. Here, I want to define two more important terms associated with diagnostic tests, the positive and negative predictive value.

As a quick review, a diagnostic test is an inexpensive, fast, and/or convenient way to determine whether a patient has a disease. To assess the performance of a diagnostic test, a gold standard is also evaluated at the same time. The gold standard is an expensive, slow, or inconvenient way to assess disease, but the gold standard is generally presumed to measure the disease without error. The positive predictive value (PPV) of a test is the probability that the patient has the disease when restricted to those patients who test positive.

In many settings, the diagnostic test can produce only two results: a positive result (T+) or a negative result (T-). The gold standard frequently indicates only two results as well: either the presence (D+) or absence (D-) of disease. You can display these results in a two by two table.

If the description so far seems a bit simplistic, that's true. There are settings where the diagnostic test can have three or more results, for example, and this does not complicate things too much. I'll talk about this case in a future newsletter.

More troublesome is when the gold standard is imperfect and does not classify without some error. This case needs to be handled with great caution.

The positive predictive value (PPV) of a test is the probability that the patient has the disease when restricted to those patients who test positive.

Do not calculate the positive predictive value on a sample where the prevalence of the disease was artificially controlled. For example, the PPV is meaningless in a study where you artificially recruited healthy and diseased patients in a one to one ratio.

The positive predictive value usually suffers greatly when examining a population where the prevalence of the disease is rare. Here's an example that shows why this is the case.

In the above diagram, patients with disease are on the left side, those testing positive (true positives) at the top and those testing negative (false negatives) at the bottom. You can see that the test does pretty well with patients who have the disease, since true positives outnumber false negatives by 9 to 1. This corresponds to a sensitivity of 90%. Healthy patients are on the right side of the diagram, with those testing positive (false positives) at the top and those testing negative (true negatives) at the bottom. The test does reasonably well with healthy patients, though not quite as well as with diseased patients. For every eight patients who test negative in this group, there are only two who test positive. This corresponds to a sensitivity of 80%.

In a clinical setting, of course, you do not know the result of the gold standard. So the natural question to ask is what conclusions might you draw if a patient tests positive. Among the patients who test positive, 36 are true positives and only 12 are false positives. So you would estimate the probability that this particular patient has a disease at 75%.

Consider a case, though, where the prevalence of the disease is much lower.

In the above diagram, the prevalence is 10% not 40%. The sensitivity and specificity are still the same, but with the much smaller pool of patients with the disease, the 9 true positives are swamped by the 18 false positives. So a positive result would lead to an estimated 67% probability that the patient is healthy!

It's hard to illustrate here, but when the prevalence sinks to 1% or 0.1% even the most sensitive and specific test will have the same type of problem.

When you are using a diagnostic test in the real world, you need to estimate the general prevalence of the disease, but with possible modifications to account for the demographics of the patient you are looking at (males are more likely to have asthma than females, for example) and modifications to account for where you are currently practicing medicine (primary care doctors see a broadly diffuse group of patients and would expect lower prevalence than in a secondary or tertiary care setting).

**3. Understanding the interaction of two continuous
variables**

I was asked to help on a research project that involves the interaction of two continuous variables. To make any progress, I had to explain what an interaction between two continuous variables in a linear regression model really means. In this case, it was believed that one variable was an effect modifier. That means that the relationship between two primary variables changes depending on what the value of the effect modifier would be. Here's a simple example.

The upper left panel of this plot shows all of the data. There is a moderately strong positive association between the two variables. The upper right panel looks at a subset of the data where the "effect modifier" is low. The two lower panels look at a subset of the data where the "effect modifier is moderate or high. Although the data may shift around from side to side, notice that the same moderately strong positive association persists within each subgroup. This is an example where the "effect modifier" is not really an effect modifier (which is why I put that term in quotes). Contrast the above with a different example.

Here the nature of the relationship between X and Y changes, depending on the value of the effect modifier. There is a strong linear relationship between X and Y when the effect modifier is low and a weak linear relationship when the effect modifier is high. You can construct more extreme examples than this, such as there being a positive relationship between X and Y for one value of the effect modifier and a negative relationship between X and Y for a different value of the effect modifier.

I don't mean to imply that interactions and effect modifiers are interchangeable terms. An interaction actually can represent something much broader in scope than an effect modifier.

So how do you fit an interaction model in linear regression? The answer is multiplication. A two variable model without an interaction is defined as

where β

_{0}represents the intercept, β_{1}represents the slope for the first independent variable, and β_{2}represents the slope for the second independent variable. A two variable model with an interaction is defined aswhere β

_{3}represents the interaction effect of the two independent variables. It is easier to understand the interaction term, though, if you center the data (subtract away the means of the independent variables) before you multiply them together.Focus your attention solely on this product term

This product will produce positive values if both terms are positive or both terms are negative. So the product term is positive if both independent variables are simultaneously above average or if both independent variables are simultaneously below average. Think of these as concordant pairs of independent variables. Likewise, the product term is negative if one independent variables is above average and the other one is below average. Think of these as discordant pairs of independent variables.

If the coefficient associated with the interaction term is positive (a positive interaction) that indicates an additional boost in the regression model for the concordant pairs of independent variables above and beyond the effect of each variable separately. This can sometimes be thought of as synergy or the whole being greater than the sum of the parts. This interpretation, however, may be overly simplistic in some contexts, so be cautious and think before you automatically claim that a positive interaction is evidence of synergy.

A negative term (a negative interaction) indicates an additional boost in the regression model for the discordant pairs of independent variables above and beyond the effect of each variable separately. This can sometimes be thought of as antagonism. One variable works well (has a positive effect) in the absence of the other variable, and vice versa, but when both variables are large, they compete with one another and largely cancel each other out. Again, this is a possible interpretation, but it may not fit in all contexts.

Here is a geometrical perspective on interactions. First, examine the surface shown below, which corresponds to no interaction.

The equation for this surface is

The equation tells you to start at 40. Add one for each unit that X

_{1}is above average or subtract one for each unit that X_{1}is below average. Do a comparable addition/subtraction for X_{2}. The left corner of the surface, corresponding to X_{1}= 5 (5 units below average) and X_{2}= 3 (2 units below average) produces a value of 40 - 5 - 2 = 33. The corner of the surface all the way in the rear, corresponding to X_{1}= 5 and X_{2}= 7 produces a value of 40 - 5 + 2 = 37. The corner of the surface sticking out in the front, corresponding to X_{1}= 15 and X_{2}= 3 produces a value of 40 + 5 - 2 = 43. Finally, the right corner, corresponding to X_{1}= 15 and X_{2}= 7 produces a value of 40 + 5 + 2 = 47.The surface shown above is called a plane. It can be thought of as a series of parallel lines in the X

_{1}direction and also as a series of parallel lines in the X_{2}direction. For example, when you travel from the left corner to the front corner, you see an increase from 33 to 43 and when you travel from the back corner to the front corner you see a similar shift from 37 to 47.The surface shown above is comparable to the first set of plots shown at the very beginning of this page. In that data set, there was the same moderately strong positive association for low, medium, and high values of the effect modifier.

Now let's examine a surface with a positive interaction.

The equation for this surface is

The product term tells you to calculate the extent to which X

_{1}and X_{2}are above/below average, multiply those extents and add half of that amount to Y. So the left corner, corresponding to X_{1}= 5 (5 units below average) and X_{2}= 3 (2 units below average) produces a product of (-5)(-2) = 10. Add half of this (5) to Y in addition to the amount you would add/subtract based on the individual values of X_{1}and X_{2}. Thus, the left corner is now 38 instead of 33. Similarly the right corner is now 52 instead of 47. The discordant corners: the front and back corners corresponding to X_{1}above average, X_{2}below average and vice versa, see a decline of 5. These values are now 38 instead of 43 and 32 instead of 37.Imagine a flat sheet of paper hovering at an angle in the air. Now push the two concordant corners upward and flex the two discordant corners downward at the same time. It curves the surface into a shape somewhat evocative of a saddle. It may not be too apparent in this particular figure because of the orientation and the relatively small magnitude for the interaction term.

With this surface, you can no longer see a series of parallel lines in the X

_{1}or X_{2}direction. The relationship between X_{1}and Y when X_{2}= 3, corresponding to the line connecting the left and front corners is a perfectly flat relationship since the values at those two corners are both 38. The relationship between X_{1}and Y when X_{2}= 7, corresponding to the line connecting the back and right corners, in contrast is very steep, the values increase from 32 at the back corner to 52 at the right corner.Now take a look at a surface corresponding to a negative interaction.

The equation for this surface is

This formula produces the opposite effect. The concordant corners (the left and right corners) are pushed down by 5 units and the discordant corners are pushed up by 5 units. The values for the left, right, front, and back corners are 28, 42, 48, and 42, respectively.

Again with this surface, you can no longer see a series of parallel lines in the X

_{1}or X_{2}direction, but the pattern is different. The relationship between X_{1}and Y when X_{2}= 3 is steep since the values change from 28 at the left corner to 48 at the front corner. The relationship between X_{1}and Y when X_{2}= 7, corresponding to the line connecting the back and right corners, in the one that is flat now, since the value is 42 at both the back and right corners.Go back and look at the data for the second example. The relationship between X and Y was strongest when the effect modifier was low and weakest when the effect modifier was high. This suggests antagonism, or a negative interaction similar to the one shown just above.

**4. Monthly Mean Article (peer reviewed): Overdiagnosis in
Cancer**

H. Gilbert Welch, William C. Black.

Overdiagnosis in Cancer. J. Natl. Cancer Inst. 2010:djq099.Abstract: "This article summarizes the phenomenon of cancer overdiagnosis--the diagnosis of a "cancer" that would otherwise not go on to cause symptoms or death. We describe the two prerequisites for cancer overdiagnosis to occur: the existence of a silent disease reservoir and activities leading to its detection (particularly cancer screening). We estimated the magnitude of overdiagnosis from randomized trials: about 25% of mammographically detected breast cancers, 50% of chest x-ray and/or sputum-detected lung cancers, and 60% of prostate-specific antigen-detected prostate cancers. We also review data from observational studies and population-based cancer statistics suggesting overdiagnosis in computed tomography-detected lung cancer, neuroblastoma, thyroid cancer, melanoma, and kidney cancer. To address the problem, patients must be adequately informed of the nature and the magnitude of the trade-off involved with early cancer detection. Equally important, researchers need to work to develop better estimates of the magnitude of overdiagnosis and develop clinical strategies to help minimize it."[Accessed April 28, 2010]. Available at: http://jnci.oxfordjournals.org/cgi/content/abstract/djq099v1.

**5. Monthly Mean Article (popular press): The Data-Driven
Life**

Gary Wolf.

The Data-Driven Life. The New York Times. 2010.Excerpt: "And yet, almost imperceptibly, numbers are infiltrating the last redoubts of the personal. Sleep, exercise, sex, food, mood, location, alertness, productivity, even spiritual well-being are being tracked and measured, shared and displayed. On MedHelp, one of the largest Internet forums for health information, more than 30,000 new personal tracking projects are started by users every month. Foursquare, a geo-tracking application with about one million users, keeps a running tally of how many times players �check in� at every locale, automatically building a detailed diary of movements and habits; many users publish these data widely. Nintendo�s Wii Fit, a device that allows players to stand on a platform, play physical games, measure their body weight and compare their stats, has sold more than 28 million units."[Accessed May 1, 2010]. Available at: http://www.nytimes.com/2010/05/02/magazine/02self-measurement-t.html.

**6. Monthly Mean Book: Voodoo Histories**

David Aaronovitch.

Voodoo Histories. Random House; 2010. Note: This book is not directly about Statistics. It covers a closely related topic, critical thinking. This book shows how people will selectively comb through the evidence to fashion rather bizarre theories.Excerpt: "Our age is obsessed by the idea of conspiracy. We see it everywhere - from Pearl Harbour to 9/11, from the assassination of Kennedy to the death of Diana. Bookshop shelves threaten to collapse under the weight of texts devoted to proving myriad conspiracy theories true, while even quality newspapers and serious TV channels are prepared to give them credence. For David Aaronovitch, there came a time when he started to see a pattern. These theories used similar dodgy methods with which to insinuate their claims: they linked themselves to the supposed conspiracies of the past (it happened then so it can happen now); they carefully manipulated their evidence to hide its holes; they relied on the authority of dubious academic sources. Most importantly, they elevated their believers to membership of an elite - a group of people able to see beyond lies to a higher reality. But why believe something that entails stretching the bounds of probability so far? Surely it is more likely that men did actually land on the moon in 1969 than that thousands of people were enlisted to fabricate a deception that they did. In this entertaining and enlightening book - aimed to provide ammunition for those who have found themselves at the wrong end of a conversation about moon landings or twin towers - Aaronovitch carefully probes and explodes a dozen of the major conspiracy theories. In doing so, he looks at why people believe them, and makes an argument for a true scepticism: one based on a thorough knowledge of history and a strong dose of common sense."

**7. Monthly Mean Definition: What is socioeconomic status?**

I'm not an expert on socioeconomic status (SES) but when someone asked me how to best measure it, I did a bit of research. SES is an aggregate measure of an individual or family that incorporates three major factors:

- income,
- education, and
- occupation.
Typically, these three factors are all indicating roughly the same thing, but in today's economy, you may see someone with a PhD serving up fries at McDonald's.

Other items might be an indirect indicator of SES. A person's insurance status, for example, could be used with no insurance or government subsidized insurance being a marker of lower SES. Home ownership could be an indicator of higher SES. Geographic location could also be an indirect indicator of SES, as certain areas tend to have a higher concentration of well paid, highly educated individuals.

SES is an important variable in many health research studies, because SES is strongly associated with many health outcomes. If you fail to account for SES properly in these studies, then effects due to differences in SES may be falsely attributed to other factors.

**8. Monthly Mean Quote: When we meet a fact...**

"

When we meet a fact which contradicts a prevailing theory, we must accept the fact and abandon the theory, even when the theory is supported by great names and generally accepted" Claude Bernard, as quoted at http://en.wikipedia.org/wiki/Claude_Bernard.

**9. Monthly Mean Unsung Hero Award: Martin Holt**

Martin Holt started an Internet discussion group, MedStats in 2005. You can participate in the discussion via email or you can go to a website to read and comment: http://groups.google.com/group/MedStats. It is amazingly difficult to run a group like this and to enforce a reasonable set of ground rules on what types of messages are appropriate/inappropriate. Without those rules, however, the MedStats discussion group would descend into chaos. Dr. Holt has done an admirable job navigating the group through many controversies and has done this with a touch that is neither too firm nor too soft. I learn a lot by reading the questions that people pose, trying to answer some of them in a short but coherent response, and watching as others provide answers to questions in areas that I know relatively little about. MedStats is a valuable resource in my continuing professional education and it is made possible through the tireless efforts of Dr. Holt.

**10. Monthly Mean Website: Centre for Multilevel
Modelling (CMM)**

Hilary Browne.

Centre for Multilevel Modelling (CMM).Excerpt: "The Centre for Multilevel Modelling (CMM) is a research centre based at the University of Bristol within the Graduate School of Education, the School of Geographical Sciences and the Department of Clinical Veterinary Science and forming part of the The Bristol Institute of Public Affairs (BIPA)" [Accessed December 5, 2009]. Available at: http://www.cmm.bristol.ac.uk/.

**11. Nick News: Nicholas buys and builds his own
basketball hoop**

Here's a picture of Nicholas taking a shot at his new basketball hoop. He helped buy it and helped put it together. Read the full story at

* www.pmean.com/personal/Hoop.html

As a bonus, take a look at the pictures of the Back Porch Cloggers, a group I belong to.

* www.pmean.com/personal/Cloggers.html

If you're in the Kansas City area, come see us perform at the Deanna Rose Children's Farmstead on Saturday, June 12 at 11am. We'll be performing at the dairy barn.

**12. Very bad joke: Three people are brought in...**

Three people are brought in for a job interview, a lawyer, an economist, and a statistician. The interviewer asks the lawyer "What is one plus one?" The lawyer responds, "In matters of commerce, the abiding precedent is a Supreme Court ruling in 1867 that established prima facie evidence that one plus one equals two. The interviewer was impressed. She then brought in the economist and asked "What is one plus one?" The economist replied, "If you believe in the efficient markets hypothesis, then you must hold that one plus one equals two." The interviewer was even more impressed with this answer. Then she brought in the statisticians and asked "What is one plus one". The statistician looks all around, gets up and shuts the door to the office and then quietly whispers "What do you want it to be?"

I can't claim credit for this. It is an old joke and you can find variations of it where the third job candidate is an economist, an epidemiologist, etc.

**13. Tell me what you think.**

How did you like this newsletter? I have three short open ended questions at

* https://app.icontact.com/icp/sub/survey/start?sid=6342&cid=338122You can also provide feedback by responding to this email. My three questions are:

- What was the most important thing that you learned in this newsletter?
- What was the one thing that you found confusing or difficult to follow?
- What other topics would you like to see covered in a future newsletter?
Only one person provided feedback to the last newsletter. That person liked the articles I had highlighted (Can we rely on the best trial? A comparison of individual trials and systematic reviews, and Convincing the Public to Accept New Medical Guidelines). That person also suggested that I review some more basic review topics like Type I and Type II errors. I do have definitions of these two terms at my old website:

* www.childrensmercy.org/stats/definitions/typei.htm

* www.childrensmercy.org/stats/definitions/typeii.htm

but I still like the suggestions and will try to elaborate more on these definitions in a future newsletter.

**14. Upcoming statistics webinars**

I messed up in May with one of my webinars and want to apologize to those people who I failed to properly notify about connection details and those who had to endure some bugs caused, in part, by my lack of preparation. I'm going to simplify the webinar process and try to avoid future problems. If you are ever confused, however, about how to connect to one of my webinars, please consult the main webinar page.

* www.pmean.com/webinarsAs a way of making it up to those people inconvenienced by the previous webinar I will offer it again as a bonus webinar on July 14. The two July webinars, by the way, complement each other very nicely and represent some of my best material. I will also offer my always popular webinar on data entry and data management in August.

Webinar #1: The first three steps in a linear regression analysis with examples in IBM SPSS. Wednesday, July 14, 11am CDT.

Webinar #2: The first three steps in a logistic regression analysis with examples in IBM SPSS. Thursday, July 15, 11am CDT.

Webinar #3: Data entry and data management issues with examples in IBM SPSS.

To sign up for any of these, send me an email with the date of the webinar in the title line (e.g., "July 14 webinar").

**15. Join me on Facebook and LinkedIn**

I'm just getting started with Facebook and LinkedIn. My personal page on Facebook is

and there is a fan page for The Monthly Mean

* www.facebook.com/group.php?gid=302778306676

I usually put technical stuff on the Monthly Mean fan page and personal stuff on my page, but there's a bit of overlap.

My page on LinkedIn is

If you'd like to be a friend on Facebook or a connection on LinkedIn, I'd love to add you.

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