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Wednesday, May 1, 2013

The GUIDE: How to Write a Research Grant Proposal: Part 5 - Research Subjects: Animal and/or Human [Full link to blog for email clients.]

One of the chief complaints leveled by animal rights groups at animal research is that it (A) repeats already known studies, and (B) uses excessive numbers of animals.

That is simply not true, and there is a component of grant proposals in which issues such as this are discussed.  Welcome to:

How to Write a Research Grant Proposal:  Part 5 - Research Subjects: Animal and/or Human

Unless a project is working with nonbiological materials, or invertebrates (i.e. without a spine: microorganisms, shellfish, worms, cell cultures, etc.) the proposal should include sections justifying the number of subjects used in the study, and describe how they are treated.   We'll start with animals today, and continue with human subjects next week.

In the case of animal subjects, the section of an NIH grant application is labeled "Vertebrate Animals" and it starts back with the selection of the type of animal, i.e. the species, rat, mouse, cat, dog,pig, sheep, armadillo, rabbit, rhesus monkey.  Animals are selected for experiments for two reasons - relevance and translation.  Relevance means that the disease or condition under study is known to affect that animal; translation means that the specific organs or structures studied within those animals are similar enough to humans that what we learn in the animals can be "translated" to humans.  Rats and mice are good for simple behaviors and brain studies, but more complex brain functions often need to be studied in monkeys and other nonhuman primates for "translation" reasons.  The selection of other species likewise follows from relevance and translation - armadillos have nearly the same reaction to the leprosy bacillus as human; the sheep placenta is well suited to study of pregnancy; the size and function of heart and circulatory system make dogs the species of choice for "cardiothoracic" studies; and the delicate skin and bones of the pig's ear are excellent for surgical research.  

Next, up is a justification of the number of animal subjects used.  This goes back to each of the Aims and experiments proposed.  How many animal subjects must be tested in order to ensure that the data obtained from that experiment can stand up to statistical validation?  I touched on this in the Friday blog two weeks ago (
The Power Function (D = fP * σ / √n) relates the size of the effect to be measured to the population standard deviation and the number of subjects.  In the equation above: D = the difference in means that we want to consider to be a "real" effect; fP = a constant from the Power Function table (found in most statistics textbooks) that is selected for a particular level; σ = the anticipated standard deviation (measure of randomness) of the measurements that I am making; and n = the square root of the number of subjects I will study (or measurements I will make).  For animal behavior, I like to work with a Power = 90%.  The fP function is exponential, it becomes very large as Power approaches 100%, so 90% is quite reasonable.  fP for 90% Power = 3.6.  
A real-world example of the calculation of statistical power: 
Given n = 10 animals, σ = 0.5 Hz difference in neuron firing rate, and fP = 3.6, the minimum difference (D) that I can reliably detect as significant in firing rate is 0.56 Hz. 
As I go on to describe, if I can estimate D and σ, then I can also calculate how many subjects I need to test to achieve a particular level of Statistical Power.  Next I look at the experiments proposed and decide whether each group to be tested needs to be different, or whether I can use the same subjects with different test (this is a good idea since it not only reduces the number of subjects used, it can also act as a "control" since experiments that test A, B, and C in the same subjects have statistical advantages over tests that use a different set of subjects for each test.

Next comes the veterinary section... each research institution is required by U.S. law to have a staff veterinarian (or even a whole department) to oversee the health of the animals.  The Vertebrate Animals section must describe the plan for caring for healthy and sick animals, who is responsible for the care, how animals will be humanely euthanized, as well as what criteria are used to make those decisions.  

As a final assurance of humane care, the section includes date of approval and references to the documentation required by the Institutional Animal Care and Use Committee of the research institution.  The IACUC protocol is a greatly expanded version of the Vertebrate Animals text containing complete description of every animal procedure (surgical, behavioral, etc.) cross-referenced to each experiment and animal subject used.  

Each research grant must therefore justify the use of animal subjects, and provide assurances that those animals will be treated humanely.  The grants are backed up by a review process at each research institution that reviews each procedure performed on animals.  The grant review process further reinforces this by reviewing the science as well.

Next week, we'll continue 
How to Write a Research Grant Proposal:  Part 5 - Research Subjects: Animal and/or Human

by looking as the Human Subjects section.

Until then, stay tuned for more science news and commentary!

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