- Dale's Law--each neuron releases only one type of neurotransmitter.
- No new neurons are born in the adult brain.
- Inputs to the neuron occur only on the dendrites and soma.
- Outputs from the neuron occur only from axonal boutons.
- Action potentials are always initiated in the soma or axon.
- Synapses are unidirectional; there is no retrograde signaling.
- The brain is immune privileged.
With this context, how to think about the move towards more evidence-based medicine? The Obama administration is making an effort to decide upon "best practices" in medicine as evidenced by research, and then to nudge doctors towards using those "best practices" by a series of governmental carrots or sticks.
Dr. Jerome Groopman discusses the potential pitfalls to this idea in this month's New York Review of Books. Not only is the literature often (usually?) wrong, it is also inadequate. Clinical studies are frequently restricted to patients with only one condition, or to selected subsets of patients (most glaringly, men); whereas in reality, many people have multiple ailments at a given time, and women, or poor people, or underrepresented minorities, have an irritating propensity to respond differently to treatments than do the more homogeneous clinical populations.
I'm not a doctor, but as a researcher I know how much literature is going to be disproven a few years down the road. Furthermore, basic science research is usually far superior in quality to clinical trials, in large part due to the laboratory setting where one can actually hold all variables constant except for the one under study--far from true in a clinical setting.
But at the same time, why do we even bother trying to figure out the best way to treat a disease if we're not going to use that information? I support Groopman's plea that doctors should have significant leniency to pursue the course of treatment that seems best to them, even if it deviates from "best practices" as currently evaluated.
But I'll go one step further (and this is a naive suggestion from someone who knows next to nothing about medicine, really): the number and type of clinical trials should be vastly expanded, by virtue of keeping tabs on the success of procedures at clinics and hospitals all over the country. We already do this with some types of procedures (close to my heart is sart.org, which tracks IVF success at different locations), but we aren't going far enough. We should be tagging all these outcomes with detailed patient information, ideally using a unique identifier for each patient that allows us to track patients wherever they go.
Then, put the army of supernumerary biomedical Ph.D.s to work. They can easily learn how to sift through these massive datasets to identify what treatments work for 35-year-old white men with elevated blood pressure but not for 60-year-old Asian women with fallen arches.
Effectively, clinical trials designed by one or a few doctors, occurring in a small number of patients, would be a thing of the past. The dreadful meta-analysis of twelve crappy published studies, which is what we currently rely on to devise most "best practices," would vanish.
There are probably a lot of reasons, including patient privacy, why this can't ever happen. But it would completely transform biomedical research. Basic scientists mostly look down their noses, and rightfully so, at the quality of clinical trials--but this approach would give clinical trials a sample size far beyond even the most ambitious basic science research. Rigorous researchers might actually want to be involved with medical science.
Especially now that we've come up with a whole new set of fundamental principles in neuroscience, and this time they're definitely right.
11 comments:
I have a comment about wanting to expand clinical trials. My spouse was in his mid 20s and developed a rare stomach tumor, one that had apparently NEVER been seen in anyone younger than 35. Successful complete removal followed. He was asked to participate in a clinical trial that would test a medicine that showed some promise for reducing reoccurrance rates. We, being research engineers, agreed to the study, but then found out that cat scans were required every 6 months, and the trial could not cover the cost (according them: because it was funded by the gov't, not a company, there wasn't money). And we, being poor grad students, had crappy health insurance who wouldn't pay for the scans. So, he didn't do the study. And a wonderful opportunity to study a very rare case in medicine was lost.
I always wonder if there is some researcher(s) out there, that this type of tumor is their whole life and they would have jumped at a chance to study his case.
So my questions are (which i know can't be answered): who pays for the trial and how do you make sure lots of cases are included?
As the spouse of a physician, I don't see these "best practices" as necessarily aimed at just having new knowledge spread throughout the medical practitioner community.
Instead, best practices are a way to reduce the "defensive" practice of medicine. If a doctor can point to some promulgated "best practices" flowchart, and they follow that, then they will be less worried about not initially covering bases that are possibly, but unlikely, outcomes.
Think of it this way:
some set of clinical presentations result in 90% of patients needing x treatment (which just happens to be cheaper), while the other 10% will fail that treatment and require something else (more expensive).
Currently, there's a lot of pressure on docs to treat everyone as if they're in the 10% case. Just in case.
A set of best practices would act to cover docs by letting them first start as if the patient will be in the most likely category, and help them in the case where those 10% who failed their initial treatment can't come back and say, "well, if you had just treated me earlier, my bad outcome wouldn't have happened."
There is a big, huge really, lab for clinical and epidemiological data of the kind you are asking for. That lab is called Scandinavia (there are some other places as well, but that's not where I am at).
Everyone has unique identity numbers, and most major diseases have population wide registries; cancer, heart failure, end stage renal disease etc. In addition, there are birth and cause of death registries so that you can keep tabs on the complete population.
However, the studies thus made cannot be construed as randomised clinical trials. They are by necessity open lable, case-control studies. Most are retrospective studies, which are weaker scientifically than prospective studies.
What we see happening on the clinical study front is that studies get bigger and bigger. The latest hypertension trials are nudging 20000 patients per group. Further, in many modern trials much of the subgroup analysis is pre-defined, which provides a solid scientific basis for using it to study smaller population groups.
So some of what you (and Obama) are asking for is already happening. What you might hope for is that it will be quicker and better done with the White House, and therefore more money, behind it.
# 8. Action potentials are all-or-none.
Or not.
There was a good article in the NYT Magazine several weeks ago about a hospital in AZ (?) that put specific protocols in place for heart disease. Much, much better outcomes for patients, but the hospital is losing MONEY on the deal because they aren't making people sicker. So there's not much incentive for other hospitals to replicate it.
One of the problems is just implementing protocols to do common-sense things we know keep patients healthier--like washing hands. Even this would be a huge step in the right direction.
I think funding would be the hardest part of your idea. Clinical trials are very expensive to run.
As for implementing best practices in medicine, I'd be happy if as a first step we simply stopped implementing proven BAD practice in some areas. The management of labor and delivery is one such area- a lot of things that have been shown to be bad ideas (laboring on your back, inducing before the cervix ripens, etc) are routinely done at some places.
Michael H--this is exactly what I'm thinking of. I thought it probably was going on elsewhere but didn't know where. Yes, retrospective are weaker than prospective, but the sheer numerical power must be fantastic.
But I doubt we'll persuade Americans to accept results from commie liberal European countries, no matter how relevant. Sigh. Of course the US has a more diverse population and potentially more complex results, but still it'd be great if we could use your results before getting our own data...
Kate, I'm relieved to hear your husband recovered. Asking the patient to bear the costs sounds unusual to me, but that might be common--doctors? I suppose usually the patient's insurance might be expected to cover it, and thus it was the low-coverage insurance that caused the problems...classic "under-insurance" caused by the horrible US system.
Nat, interesting perspective. Groopman's article was all about his fear that doctors would be forced to follow bad "best" practices--didn't touch on this issue at all. Certainly anything to reduce malpractice costs would be fantastic.
Cloud, whole point is that there wouldn't need to be trials per se--just a comprehensive tracking system. Expensive to put in place but then cheap to analyze the scads of data....but yeah, often seems that women's health is, surprise surprise, less respected than men's...
There are definitely significant gaps in clinical research. A specific example: Most of the clinical research (genetics, markers, etc.) in lupus has been done in small groups of Caucasians, but there is a much higher prevalence of lupus in African Americans. Some researchers are trying quite hard to address such issues.
An important point on clinical trials is that in some cases, the money is there, but the participants are not. Academic medical research centers struggle to recruit patients to trials, and sometimes can't even run them due to lack of participation.
Aside from this, the model that Dr. Jekyll describes is reminiscent of reforms proposed (at least by academics) for FDA drug approval (and practiced in Europe), in which you do fewer trials but rigorously track results and adverse effects after drug release.
I'm sorry, I misunderstood your plan. If you want to track health data without signing people up for specific trials, you'd have to do some work on HIPAA compliance. This is probably manageable. But you'd also have to convince the tinfoil hat brigade that the government isn't out to get them by tracking their health data. Someone would probably say that the government was going to start taxing people based on health status or some other such nonsense, and the whole scheme would go down in a blaze of conspiracy theory nutjobbery.
Biochem belle- Pharma companies do rigorously track adverse events, or at least try to, even here in the US. They rely on doctors to report the events for the most part, although they will also take direct reports from patients. I know this because I did some work on these databases for a pharma company once. They had data going back years and years, as required by the FDA, and any work that touched that data had to follow strict guidelines (also required by the FDA).
I'm a little fuzzier on what analyses they are required to do and what they have to report to the FDA. However, a lot of the big drug safety blowups recently have come from things the drug companies themselves reported.
Expanded clinical trials sounds great but
WHO is paying?
That's why our system is so costly already
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