The value of p

The value of p

In biomedical research statistics are a funny thing. The post below touches on some of them. One thing that I’ve found that is bad but not necessarily fraud, is that many researchers learn a statistical method from a mentor or journal and use only that method, e.g., Student t-test. A t-test is perfectly fine when comparing two groups. If you have more than two groups, you have to switch to an analysis of variance, ANOVA or something else. In some fields and journals, the problem is bad enough that even reviewers don’t catch the statistical flaw. However, all is not doom and gloom. Many if not all universities have a group of statisticians on hand to help you design your study, i.e., statistical method, before you do the research. Many large grants want evidence of this, e.g. in a power calculation.

Here are a few older posts on statistics.

Beer + statistics (science) + history, FTW.

http://goo.gl/EC0Y37

Analysis of Meta-analysis

http://goo.gl/SGAmAu

Bad science → bad headlines

http://goo.gl/ojW213

Here are some examples of publications that don’t quite understand what significance means. http://goo.gl/AgWTRl

#ScienceEveryday  

Originally shared by Joerg Fliege

A peculiar prevalence of p-values

Now whats a p-value?  In laymans terms, it is a number saying that a particular hypothesis (“All sheeps are black”, “All math teachers are jerks”, “Aspirin helps against cancer”, etc) is not completely bats… crazy.  It roughly goes like this. You make up a hypothesis (see above) that you really do not like, and you gather some data (e.g. some sheep, or some math teachers). The p-value corresponding to this hypothesis and this data set then tells you how probable it is to randomly stumble upon that particular data set under the assumption that the hypothesis is true. Small p-values tell you that the hypothesis is probably wrong, which is what you wanted to show anyway.

There is big money in small p-values. Its what you need to ‘show’ that a particular treatment for a particular ailment works in order to bring your pills to the market. [Insert cheap joke about big pharma and certain dysfunctions here.]

Now whats a small p-value?

Well, Ronald Aylmer Fisher wrote the following in The Journal of the Ministry of Agriculture, in the year of the Lord 1926:

If one in twenty does not seem high enough odds, we may, if we prefer it, draw the line at one in fifty (the 2 per cent. point), or one in a hundred (the 1 per cent. point). Personally, the writer prefers to set a low standard of significance at the 5 per cent point, and ignore entirely all results which fail to reach this level. A scientific fact should be regarded as experimentally established only if a properly designed experiment rarely fails to give this level of significance.

In other words, Fisher pulled the number 1/20 = 0.05 out of his ass thin air and was honest about it. Since then, people have followed Fisher’s words as reported in the reputable Journal of the Ministry of Agriculture. Not with pulling numbers out of various orifices, but with sticking to p=0.05 as the special value that shows ‘significance’, like a religious sermon.

Now lets have a look at p-values reported in various recent papers. Say, 3627 of them. This is where the histogram comes from [1]. (The original paper [2] is behind a pay wall. Thank you, Taylor & Francis.)

Look, too many p-values less than 0.05!  And too few above 0.05!  How peculiar, and utterly surprising!

Some possible explanations [1]:

Publication bias. Report a p-value just above 0.05? Referees will shoot you down.

Give up. Found a p-value just above 0.05? Don’t bother writing up.  Because see above.

Tweaking. Fiddle around with your analysis until you make it below 0.05.

Dynamic sample size. Fiddle with the sample size until you make it below 0.05.

Slice and dice. Only report p-values for ‘appropriate’ subsets of data.

Outliers. Only report outliers.

One item is missing from this list: Fraud.

Caveat: the 3627 reported p-values all come from psychology journals. Be careful before you start laughing and point fingers at that particular discipline. Are you sure this stuff doesn’t happen in your neck of the woods?

[1] http://www.graphpad.com/www/data-analysis-resource-center/blog/a-peculiar-prevalence-of-p-values-just-below-051/

[2] http://www.ncbi.nlm.nih.gov/pubmed/22853650

Empathy: helps on the way

Empathy: helps on the way

I came across an article in Psychology Today discussing the  Cambridge Declaration on Consciousness. You can read more about the declaration in the links below. Basically a group of scientists met in Cambridge and proclaimed their support for the idea that some animals have a consciousness. Don’t get carried away and confuse that with intelligence. Also the declaration doesn’t say anything about the treatment of animals. I was a bit annoyed that the Psychology Today article kept mentioning abuse, as if to stoke the ire of the animal rights activists. It’s interesting that the article mentions the Animal Welfare Act. It is true that there are some animal studies that the general population might find unsettlingly. However, there are so many regulations on what you can and cannot do when it comes to animal research, that I find the term “abuse” to be disingenuous. Contrast that with the article from io9.

I’m in total agreement that some animals have consciousness and that they should be treated humanely. Here’s an excerpt from the declaration.

The absence of a neocortex does not appear to preclude an organism from experiencing affective states. Convergent evidence indicates that non-human animals have the neuroanatomical, neurochemical, and neurophysiological substrates of conscious states along with the capacity to exhibit intentional behaviors. Consequently, the weight of evidence indicates that humans are not unique in possessing the neurological substrates that generate consciousness. Nonhuman animals, including all mammals and birds, and many other creatures, including octopuses, also possess these neurological substrates.

I’ve talked about birds already (see the PET link below). The rest of this post will focus on something I shared back in December 2011. I shared it privately as I was new to G+. So I’m redoing it here. The image below is a screen capture of a study by a group at the The University of Chicago The video is in the link below, Helping your fellow rat.. Bartal et al showed that rats can demonstrate empathy by having a free rat rescue his or her cagemate, which is placed in a plastic restrainer. Once the rats learned to open the restrainer, they only opened it if there was a cagemate in it, i.e., if it was empty or had an object inside they left it locked. Also, when presented with a locked cagemate and a locked piece of chocolate, the free rat would unlock both and share the chocolate. That’s better than many politicians. Rats were initially startled by the door opening. In later repeated tests, the rats were no longer surprised by the door opening, i.e., it was an expected outcome.

The data suggests that females are more empathetic. All of the females became door openers while only 70% of the males opened the door. Also, the females learned to open the door sooner than the male rats.

Combined with the bird studies, there is mounting evidence that animals have more going on in their brains than some people think.

Links to references:

The Cambridge Declaration on Consciousness

http://goo.gl/tXglo

Scientists Finally Conclude Nonhuman Animals Are Conscious Beings

by Marc Bekoff, Ph.D. in Psychology Today

http://goo.gl/wecrHZ

Prominent scientists sign declaration that animals have conscious awareness, just like us

http://goo.gl/tWh8t io9 George Dvorsky

Something to crow about: PET Bird Brains

http://goo.gl/8Xfg0k

Helping your fellow rat: Rodents show empathy-driven behavior 

http://goo.gl/oTwnn

Published in Science

Empathy and pro-social behavior in rats.

Ben-Ami Bartal I, Decety J, Mason P.

Science. 2011 Dec 9;334(6061):1427-30. doi: 10.1126/science.1210789.

http://www.ncbi.nlm.nih.gov/pubmed/?term=22158823

#ScienceSunday  

Don’t hyperventilate

Don’t hyperventilate

Here’s another example of some interesting science that doesn’t need any hype. The news blurb is titled Injectable Oxygen Keeps People Alive Without Breathing and was shared here: http://goo.gl/xjmeE4 I promised Rahul Roy that I would follow up after reading the full journal article. Notice the title on the journal article is less sensational, Oxygen Gas–Filled Microparticles Provide Intravenous Oxygen Delivery JN Kheir et al. Sci Transl Med 27 June 2012 http://goo.gl/9tN6yx   Techandfacts.com actually did a decent job reporting the science. The title is a little hyped but not bad. I’ve certainly seen worse, e.g., Bench to Bedside http://goo.gl/xudsu

So what is this article about, what’s the science?

❤ Lipidic oxygen-containing microparticles (LOM)

Dr. Kheir et al created microbubbles or LOMs to deliver oxygen when patients have difficulty breathing. This is an important part; it is not a blood substitute. It is not intended for trauma involving blood loss. We’ll get back to that later. What is LOM? When you make a vinaigrette you notice that oil and water don’t mix. You can shake/whisk the mixture or use an emulsifier (like mustard) to make an emulsion (a mixture of two liquids that normally don’t mix). Micelles are formed when a molecule has a hydrophobic part (doesn’t like water) and a hydrophilic part (likes water) and it’s placed in a liquid. If the liquid is water, the hydrophobic parts try to escape the water and end up on the inside of a sphere with the hydrophilic part on the outside. So the lipidic part of LOM is used to make micelles with oxygen inside. They use sound waves (via a sonicator) to disrupt the micelles enough to trap the oxygen inside of them. A red blood cell is 7-8 µm in diameter and the LOMs are 2-4 µm so they have no problem getting through the capillaries.

❤ O2 delivery vs. O2 carrier

So why is this good for short term use when there may be an issue with breathing but not in a trauma, blood loss situation? The LOMs are injected into the bloodstream where they can quickly oxygenate the blood. See the beaker of blood before and after adding LOMs (via the journal article). As the oxygen leaves the LOMs and saturates the hemoglobin in blood, they shrink. Think of a balloon releasing oxygen. The “deflated” LOMs cannot be “re-inflated” in the bloodstream (remember the sonicator was needed to get the oxygen in). You can see a deflated LOM in the lower left of the cartoon. Also carbon dioxide is not removed. In the short term this isn’t an issue. If this were needed for longer use, the CO2 would build up and make the blood acidic.

So what’s the difference between O2 delivery and an O2 carrier? LOMs are an O2 delivery system. Oxygen (or carbon dioxide for that matter) does not go back to the LOMs as they circulate. There two types of artificial oxygen carriers: hemoglobin based and perfluorocarbon (PFC). The LOMs are closer to PFC formulations.

❤ Perfluorocarbon (PFC)

A perfluorocarbon is an organic compound made up of carbon and fluorine. Emulsions of PFCs can be made that carry oxygen. Early on the emulsifiers used in PFC emulsions caused allergic reactions in people. The biggest problem with PFCs in the context of artificial blood is that the oxygen carrying characteristics require high oxygen content in the blood in order to release the oxygen. If you look at the figure below (http://goo.gl/csOsnk) you can see that you need a higher partial pressure (pO2, oxygen concentration) for the PFC relative to blood to release oxygen. Here’s a video that shows a mouse breathing liquid PFC. You might see other videos incorrectly state that it is a mouse breathing water.

Part 1 Wonders of the Human Body – BBC Explorations | Storyteller Media

❤ 2,3 diphosphoglycerate (2,3 DPG)

So what makes blood or hemoglobin so much better than PFC for oxygen carrying? A little compound called 2,3 diphosphoglycerate (2,3 DPG) is the key. It’s an allosteric effector. Allos from Greek means other and stereos means space. So an allosteric effector changes the shape or folding of a protein when bound or unbound. When 2,3 DPG is bound it shifts hemoglobin to the low affinity state for oxygen, i.e., releasing it more readily. It’s increased levels help in conditions of low oxygen/blood, e.g. traumatic blood loss.

One other tidbit, these microbubbles aren’t new. They have been used as contrast agents for ultrasound imaging, which I’ll talk about in another post. I can also talk more about hemoglobin based oxygen carriers in a future post if there is interest.

Happy #ScienceSunday