Treating Low T can be dangerous

I am bombarded with low t (low testosterone) commercials on the radio and television. There is a men’s health clinic in my city that will screen and treat men for this horrendous affliction. They guarantee greater sexual prowess and a happy marriage. What they don’t mention are the side effects that can be deadly.

An important study was published in JAMA in 2013 that showed increased cardiac risk in veterans who were prescribed testosterone. The caveat of this study is that all the patients in the study had undergone cardiac catheterization and thus were at higher risk for CAD than those who don’t undergo cardiac cath. As shown in the image below at any given point during follow-up those assigned to testosterone were at 29% greater risk of death, MI or stroke than those on no testosterone therapy. Adjusting for the presence of CAD had no effect on the estimate of outcomes. Thus, even those without CAD (by catheterization) were at increased risk of death, MI and stroke. Most patients in this study got patches or injections. Around 1% got the gel.

Survival curve for testosterone1
A new study has looked at differences in risk among different testosterone dosage forms. This was a huge retrospective cohort (544K patients): 37.4% injection, 6.9% patch, and 55.8% gel users. The outcomes of interest were myocardial infarction (MI), unstable angina, stroke, and composite acute event (MI, unstable angina, or stroke); venous thromboembolism (VTE); mortality; and all-cause hospitalization. They compared these outcomes between injection users and gel users and between patch users and gel users. They didn’t have a nonuser group but that wasn’t really needed as risk compared to nonusers has been established with the study I noted above. The results are shown in the 2 figures below.

Results 2Results 1

 

 

 

 

 

 

 

 

 

 

Using injectable testosterone was associated with increased risk of stroke, death, MI, and hospitalization compared to testosterone gel (left figure above). Testosterone patches only increased the risk of MI compared to testosterone gel (right figure above). You should look at the absolute rates in the tables in the paper as they are low and what I report above are relative rates which can be misleading.

The bottom line is that you should have a good reason to replace testosterone and not just because the patient’s T is low. You should consider the cardiovascular risk of this drug and counsel the patient on this risk (in addition to risk of prostate cancer and polycythemia). If you choose to replace T then the gel is the safest followed by patches.

Evidence-Based Teaching Principle 3: Modality Principle

The following is a slide I might use to begin teaching about p-values, type I and type 2 errors. What do you think about it? Will students learn deeply from it? (Would like to see a larger version of the slide? Please click on it)

Version 1

Version 1

Or do you think students would learn more deeply from this slide? The words at the bottom of the slide would be spoken by the instructor while the graphic is displayed.

Version 2

Version 2

Research would predict version 2 is better and will lead to deeper understanding. But why? What is different about them?

Version 1 violates the modality principle which states that people learn more deeply from multimedia lessons when words explaining concurrent graphics are presented as speech rather than as on-screen text. In version 1, the visual channel would have to simultaneously process the graphic and the printed text. This would likely overload this channel. In contrast, in version 2 the education message is split across separate cognitive channels- the graphic in the visual channel and words in the auditory channel.

Some caveats or limitations of this principle:

  1. It’s more important for novice learners
  2. It’s more important if the material is complex and presented at a rapid pace in a lecture. If the learner can control the pace of the material the modality principle is less important.
  3. Doesn’t apply if only printed words are presented on the screen (without any corresponding graphic)
  4. There are times when words should be presented on screen
    • words are technical
    • words are not in the learner’s native language
    • words are needed for future reference (e.g. directions to a practice exercise)

What’s the evidence for this? The modality principle is supported by more research than any other multimedia principle. Mayer identified 21 studies published through 2004 and found an average effect size on transfer tests of 0.97 (effect sizes > 0.8 are significant, 0.5 are moderate).

Evidence-Based Teaching Principle 2: Contiguity Principle

The following is a slide I might use to teach about interpreting a forest plot. What do you think about it? Will students learn deeply from it? (Would like to see a larger version of the slide? Please click on it)

Version 1

Version 1

Or do you think students would learn more deeply from this slide?

Version 2

Version 2

Research would predict version 2 is better and will lead to deeper understanding. But why? What is different about them?

Version 1 violates the spatial contiguity principle which states that people learn more deeply from a multimedia message when corresponding words and pictures are presented near rather than far from each other on the page or screen. In version 1 the words describing the image are at the bottom of the slide. The learner will have to look away from the graphic to find this description and then hold it in working memory (remember working memory is limited in capacity and time it can hold an object) while he looks back to the image and tries to process them together. This can overload cognitive capacity and impair learning. Version 2, on the other hand, has the words right next to the corresponding graphic thus reducing cognitive work. This is especially important when words refer to parts of on-screen graphics.

Other common violations of the spatial contiguity principle  include:

  • Feedback is displayed on a separate screen from the practice exercise or question
  • Directions to complete practice exercises are placed on a separate screen from the application screen
  • Key elements of a graphic are numbered but the legend is at the bottom of the screen

Watch the following video about how to calculate the number needed to treat. Will students learn deeply from this video?

Research would predict they won’t because the instructor violated the temporal contiguity principle which states that people learn more deeply from a multimedia message when corresponding animation and narration are presented simultaneously rather than successively. Cognitive capacity will be overloaded because the learner has to hold all of the relevant words in working memory until the animation is presented. This principle is especially important when narration and animation segments are long and when students can’t control the pace of the presentation.

What’s the evidence for this? Mayer, in Table 12.7 in the Cambridge Handbook of Multimedia Learning (2014), summarizes 22 studies on spatial contiguity published through 2012 and finds an average effect size of 1.10 (effect sizes > 0.8 are significant, 0.5 are moderate). Table 12.8 summarizes 9 studies on temporal contiguity published through 2008 and finds an average effect size of 1.22. Thus, following the contiguity principle leads to deeper understanding.

Evidence-based Teaching Principle 1: multimedia principle (Use words and pictures rather than words alone)

The following is a slide I might use to teach about one of the criteria for critically appraising a therapy study. What do you think about it? Will students learn deeply from it?

Version 1

Version 1

The multimedia principle states that people learn more deeply from words and pictures than from words alone. Why might this be? Reflect upon the cognitive theory of multimedia learning and think about why the multimedia principle leads to better learning.

Here is another version of the previous slide that better adheres to the multimedia principle. (Note: Would you like to enlarge the image? If so, please click on it). What do you think about this one? Will students learn more deeply from it or version 1?

Version 2

Version 2

Where are the words you say? They would be spoken during a lecture explaining the same information on the version 1 slide. They just aren’t typed out on the slide. Another format would be to put the written words in the notes area in PowerPoint.

Research would predict that students will learn more deeply from version 2 than version 1. Why? Remember active processing occurs where we take words and images and develop verbal and pictorial models. The words and images work together to help learners develop the models. Words alone can lead to more cognitive work for the learner to construct a model. Also, words alone might not be effective in activating prior knowledge which we need to do so that it can be integrated with our new model which then leads to learning. I have left out an important explanation here (can you guess what it is?) but it is a multimedia principle of its own and will be covered in an upcoming post.

Are all images created equal? What kind of images should I use? The answer to both of these question is that it depends. Lets focus on what you are trying to teach first. If you are trying to teach a motor skill or complicated manual tasks animated images or video seems to work better. Static images are better or just as effective as animation for everything else.  Static images seem to be better for promoting deep understanding.

Which graphic below do you think would lead to better understanding about heart function? A or B?

From Butcher. J of Educ Psychol 2006;98:182

From Butcher. J of Educ Psychol 2006;98:182

Butcher (2006) found that simpler visuals (a) led to better understanding. The simpler visual led learners to make more attempts to understand how the heart works than the complex visual. Making more attempts led to better mental models. It seems that too complex of images can overwhelm novice learners.

Some caveats or limitations of this principle:

  1. If learners can control the pace of instruction complex images promoted stronger knowledge gains (in a lecture setting where the instructor controls the pace simple images are better)
  2. Its more important for novice learners
  3. Sometimes only words can be used to explain a topic

What’s the evidence for this? Mayer, in Table 7.1 in the Cambridge Handbook of Multimedia Learning (2014), summarizes 9 studies published through 2006 and finds an average effect size on retention tests of 0.19 and for transfer tests of 1.63 (effect sizes > 0.8 are significant, 0.5 are moderate). Thus, this principle shows weaker effects for retention but good effects on deeper understanding.

Evidence-based teaching of EBM (and anything else)

I am going to have a series of posts on multimedia teaching principles. I am pursuing a master degree in instructional design and educational technology and as I am learning about instructional design I am realizing how poorly I have designed much of my teaching materials.  Furthermore, violations of the principles I will discuss in this series is very common in medical education.  Its not the fault of the instructors as they haven’t been taught these principles. For some reason in medicine we assume doctors and PhDs know how to teach.

The point of this series will be to present multimedia design concepts that have been proven in the educational literature to improve learning based on tests of retention (do you remember the content based on simple recall) and transfer (can you apply the information to solve a closely related problem).

We all teach using multimedia materials. If you put words (spoken or written) and images together in a presentation that is a multimedia presentation. So this series will be applicable to all teachers.

This first post will set the stage for future posts. The theory upon which all other posts will be based is the Cognitive Theory of Multimedia Learning by Richard Mayer.

cognitive theory of multimedia learning

The main components of this theory are as follows:

  1. Dual channels: there are 2 pathways to process information: auditory and visual ( designated in blue and green, respectively)
  2. There is limited capacity of each pathway to process information
  3. Active processing occurs in each pathway

When words or images are presented to us we first have to determine which words or images are important (or which portions of them are important).  After we select words, images, or sounds that are meaningful, we organize them in our working, active memory into verbal and/or pictorial models. We then actively integrate these models with activated prior knowledge to create new knowledge (learning).

Multimedia presentations should be designed to facilitate this process. During the remainder of this series I will present evidence-based ways to do this. I will delve further into the Cognitive Theory of Multimedia Learning when I discuss how this process is affected by each of the design principles.

Podcasting to help keep current

Intro image

I am taking a class on Multimedia as part of my Master of Educational Technology degree program. This week our assignment was to develop a podcast and I decided to make it EBM related (always make your work count twice). I used Audacity, a free audio editor and recorder, to create the podcast. There was a learning curve but I have it mostly figured out. In the past when I created all my YouTube videos I “lectured” off the top of my head. For this assignment I had to write a script first and read from it. This is much better than ad-libbing. I don’t have an verbal tics (like “uhs”) and my cadence is better.  I suggest if you do any recordings, even about things you know a lot about, make a script and read it.

Medicine Review in a Few will be a podcast series in which I review what I consider important studies in Internal Medicine.  Each episode will review one study and will last less than 10 minutes; hence the “in a few” portion of the title. I think its important to keep information that isn’t interactive and is only processed through one channel fairly short. I personally lose interest and focus with long podcasts. According to data from Stitcher.com the average listener abandons a podcast within 22 minutes.

In Episode 1 I review the ADJUST-PE study. I chose to begin my podcast series with this study because I recently used the information in this study to care for a patient. I wasn’t aware of the findings of this study until one of my residents brought it to my attention.  I plan to only review clinically useful studies and will comment on any methodological limitations of the studies that I think the average clinician wouldn’t recognize or know how that limitation impacts the study findings. I think podcasts are a good medium to review studies.

For now, the podcasts will only be posted here but if I keep up with this endeaver I’ll ultimately try to get them on iTunes.

The image I used above is from splitshire.com and requires no attribution. The music used in my podcast is royalty free from Looperman.com.

How to calculate patient-specific estimates of benefit and harm from a RCT

One of the more challenging concepts for students is how to apply information from a study to an individual patient. Students have been taught how to calculate a number needed to treat (NNT) but that isn’t often very useful for the current patient they are seeing. Usually our patients are sicker or healthier than those in the study we are reading. Studies include a range of patients so the effect we see in the results is the average effect for all patients in the study.

Imagine you are seeing Mr. Fick, a 70 yo M with ischemic cardiomyopathy (EF 20%) and refractory anemia (baseline Hg 7-10 mg/dl). He reports stable CHF symptoms of dyspnea walking around the house after about 30 ft. He reports other signs and symptoms of CHF are stable. Medications include lisinopril 20mg bid, aspirin daily, furosemide 80 mg daily, and iron tablets daily. He is not taking a beta blocker due to bradycardia and can’t take a statin due to myopathy. He has refused an ICD in the past. BP is 95/62 mm Hg, pulse is 50 bpm, weight is stable at 200 lbs. Labs done one week earlier show a stable Na 0f 125 mmol/l, K 3.8 mmol/l, Hg 8 g/dl, platelets 162 k, WBC is normal with 22% lymphs on differential, cholesterol is 220 mg/dl, and uric acid is 6.2.  Since he has severe CHF you are considering adding spironolactone to his regimen. he is concerned because he has a hard time tolerating medications. He wants to know how much it will help him. What do you tell him?

This figure is from the RALES trial, a study of spironolactone in patients with advanced CHF. Use the figure below to figure out Mr. Fick’s individual estimated risk of death if he agrees to take spironolactone.

RALES figure

There are 4 methods I will demonstrate to calculate a patient-specific estimate of effect from an RCT. First, think about what information you will need to estimate Mr. Fick’s specific benefits of spironolactone. You will need the NNT from the RALES trial and Mr. Fick’s estimated risk of death (we call this the PEER or the patient expected event rate). Where do we get the PEER of death for Mr. Fick? You use a validated prediction rule. I use Calculate by QxMD. Look in the Cardiology folder under heart failure and open the Seattle Heart Failure Model. Plug in Mr. Fick’s data and you get his 1 year expected risk of death (56%).

Method 1: Calculate patient-specific NNT using PEER: the formula for this is 1 / (PEER x RRR) where RRR is the relative risk reduction from the RALES trial (30%. To calculate that: 1-RR is the RRR). So plugging that in, Mr. Fick’s NNT is 1 / (0.56 x 0.3) = 6 (the NNT from the RALES trial is 9).

Method 2: Estimate patient-specific NNT using f: F is what I call the fudge factor. It is your guesstimation of how much higher or lower Mr. Fick’s risk of death is than that of the average patient in the study. If you say he is 2 times more likely to die then f is 2. If you think he is half as likely then f is 0.5. The way to use f is to divide the study NNT by f. This gives an estimate of Mr. Fick’s NNT. So lets just say Mr. Fick is twice as likely to die than those in the study. The NNT of the study is 9.  So 9/2 is 4.5 which I would round up to 5.

NNTs are nice but its hard to use them directly with a patient. The next 2 calculations are more useful for patients.

Method 3: use the RR  to calculate Mr. Fick’s actual risk of death: the RR of death in the RALES trial is 0.70. You multiply this by his estimated death rate and you get his expected death risk if he were on spironolactone instead of nothing. His risk of death is 56%. So 0.70 x 0.56 = 39%. So if Mr. Fick takes spironolactone I expect his risk of death to go from 56% down to 39%. That’s useful information to tell the patient.

Method 4: use the RRR to calculate Mr. Fick’s actual risk of death: This is similar to the concept above except that you have to remember that the RRR (relative risk reduction) is relative. So first you calculate how much risk is reduced by the treatment. The RRR is 30% (1-RR is RRR). Then I multiply this by the patient’s risk of death. 0.30 x 0.56 is 0.168. This 16.8% represents how much risk I have removed from the baseline risk. Now I have to subtract it from the baseline risk and I get his final risk. So 0.56-0.168=0.39 or 39%. Same number as method 3 and it has to give the same number because its just a different way of calculating the exact same thing.

I hope this is useful and now you can give patients some real numbers instead of just saying your risk is decreased by x%.

Remember you need: patients risk of the event without treatment (usually from a prediction rule or maybe the placebo event rate of the study or placebo rate of a subgroup) and event rates from the study. Then you can make all the calculations from there.