While meeting with a visiting speaker last week, the subject came up of studying biological pathways that only account for <1% of a given disease. For example, schizophrenia is a very heterogeneous disease with multiple proposed risk factors. Genome-wide association studies have been conducted to identify specific risk factors. Although these studies have been successful in identifying candidate molecules, such as microRNA-137 and then gene C4, how helpful can they be if they only contribute to a small percentage of schizophrenia cases? This made me think of a question that keeps coming up in this course: when is clinical significance more important than statistical significance? Though the studies have statistically significant results, how significant are they to the health field if they cannot help patients with schizophrenia?
I believe this problem somewhat originates from the drive to get funding from the NIH. When applying for grants, your project becomes much more appealing when a disease is attached to it. Thus, a protein that a large group of the scientific community didn't care about before becomes much more appealing when it's tied to some disease, no matter how small the percentage of risk is. As soon as you have a study showing a statistically significant result for a pathway implicated in a disease, your research gets some attention. But how much does that matter in the scheme of the actual disease when the mutation you are observing accounts for <5% of a disease?
While this may not be considered a form of "bias", I believe that attempting to put a health-related spin on research is severely affecting the way that we conduct research. Making overreaching conclusions can mislead readers and misdirect future research projects. These studies may have the right numbers and statistics, but do they have the right scientific approach of questioning?
This is a very interesting point you make, and I agree with you to some extent. I think when it comes to applying for NIH grants, having clinical relevance does not just make a grant more appealing, but it is really a requirement to get funding. This is not the case for NSF grants, it is actually quite the opposite, basic science with no direct clinical outcome is favored. I attended a seminar not too long ago where the speaker mentioned her lab used influenza as "a model" for T cell responses. My initial thoughts were that influenza is a very serious infection that is still to this day responsible for morbidity and mortality around the world. However, the research was more on the basic side of immunology and the clinical relevance was not obvious. In the end I think conducting rigorous science, regardless of obvious clinical relevance, and advancing the overall knowledge of the field is what is ultimately important.
ReplyDeleteI think in the short-term, findings that are highlighted above have very limited clinical significance - even when linked to schizophrenia. I don't think this is because schizophrenia was innapropriately linked to the experiments in order to get NIH funding, or that these risk factors do not represent the etiology of most patients' schizophrenia. Rather, I think they have limited clinical significance because we may not know how many other risk factors can interact with these to exaggerate symptoms or possibly underlie shared dysfunctions between schizophrenia and other neuropsychiatric disorders. The C4 gene, for example, may play a causal role in the pathogenesis of schizophrenia for a minority of patients, but its involvement in synaptic pruning has major implications. That's why I think that the clinical significance may be more rooted in the long-term follow-up projects and associations with other synaptic disorders. While we may not know the details of C4 involvement in other disorders right now, we do know that irregularities in synapses and dendrites constitutes a biological phenotype in a range of disorders. So, while clinical significance may be low for the majority of patients with schizophrenia right now, I wonder how much this will change in the future if looking at this risk factor in patients with diseases characterized by synaptic irregularities.
ReplyDeleteI agree with you. I think it is actually a big problem that people think that all research has to be tied to a disease or translational to be interesting or to get funded. 1. Basic research is extremely important for scientific discovery and desperately needs more funding. 2. Like you pointed out, a lot if not most of these disease correlated studies are not clinically significant. Studying the mechanism behind a rare genetic variant of a disease is my opinion is unlikely to lead to significant health improvements for the vast majority of patients with much more complex heterogenous disease presentation. I believe we see a good example of this with alzheimer's disease research. Almost all non-human research is done with models of rare early-onset genetic mutations and these cases only account 2-3% of patients. I would argue that we don't yet have ability to accurately model a complex diseases like AD so simple genetic models are a good start. I just think people have gotten way ahead of themselves in regards to the translatability of results from those studies during their quest for the ever elusive NIH grant.
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