Why most published research findings are false

So this was an interesting article published in PLoS Medicine by John P. A. Ioannidis. The article lists several reasons of why research is probably false. He argued that the smaller the sample size of your study, the less likely it is that your findings were true. Also, the number of previous studies on related work, the flexibility in the methods, the type of analysis, and the undeclared competing interests all have effects on the probability that a finding is true.

Most of what he said made perfect sense. If you have a study with only seven samples, the likelihood of the samples representing the entire population is fairly small. If you do a study with thousands of samples, your findings have more weight in their statistical significance.

There were several parts of the paper that were frustrating. For example, he didn't seem to have that many suggestions about how scientists can fix this problem. He also thinks that we should declare conflicts of interest much more, which everyone is trying to find significant results so that they can publish and earn more money, be more recognized, get that tenure, or just validate that you are spending all of your time on something significant. No one really goes into research thinking that they aren't going to find anything, otherwise, why would you study it?

He thought that flexibility in methodology makes your results invalid, I think flexibility is what makes your experiment real. Statistics works with theoretically, what is the mathematically perfect way to do this. Reality doesn't work so neat. Cell transformations have a tried and true methodology. And yet, why do so many people have difficulty transforming cells? This is due to the randomness of nature, and the fact that we are dealing with living organisms who react differently to things.

When I first read the article, I freaked out and thought, "So, my entire career is just worthless because most of my findings are probably false?!?" I feel that if so much was actually false, then it wouldn't be repeatable, we wouldn't be able to build off of it, it would appear to be flawed or fall apart. I think this paper is good to remind us that we should be careful and aim to be unbiased and as accurate as possible.

Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children

So, this past week, we read the infamously retracted paper written by A. J. Wakefield. I am going to only attribute the article to Wakefield, even though the paper was originally published with multiple authors, because all of the other authors retracted their names after they discovered Wakefield had a conflict of interest when writing this paper.
This is the article that lead to the whole "Vaccines cause Autism". There is a lot of interesting things wrong with this paper and interesting reviews of this paper. One of the main problems is that Wakefield was payed (I believe in the forms of grants) by a law firm that was planning on suing the vaccination companies. Other problems with the paper include that a bunch of the results were falsely reported, the children were never actually psychologically tested for the study to see if they had developmental disorders, and that the mothers reported the possible link between vaccination and developmental disorders.

The thing that I found most intriguing about this paper was that in the third to last paragraph the paper states, "Published evidence is inadequate to show whether there is a change in incidence or a link to the measles, mumps, and rubella vaccine." The last paragraph then goes on to state, "In most cases, onset of symptoms was after measles, mumps, and rubella immunization. Further investigations are needed to examine this syndrome and its possible relation to the vaccine." As part of the falsifying of data, if you look in the paper, some of the children started showing symptoms before they were vaccinated, and for the rest, I am going to assume that the symptoms just didn't exhibit themselves until after vaccination. This is probably due to children being incredibly young when they are immunized and don't develop the ability to talk and walk and read until they are older than that.

One of the most interesting results of this paper, was the decrease in parents having their children vaccinated. There has also been a huge increase in the amount of children catching these diseases. I think that someone should do a study comparing the number of incidents of the diseases and the percentage of children vaccinated, before this paper was published and after this paper was published. This resulting study would have a very strong correlation between children getting these diseases and children not getting vaccinated. (This study would have to take into account that if someone is unvaccinated, then there is a greater chance of the people they associate with getting the disease, even if the associates were vaccinated.)

I think one of the worst outcomes of this paper is the lack of funding that autism has now received. The general public is still under the assumption that vaccinations cause autism, so clearly they don't need to fund autism research if they already know the cause, right? Wrong.

I also thought it was interesting the amount of the paper that focused on the digestive problems of the children. I was previously unaware that children with autism tended to have digestive problems. I thought it was interesting that the children actually had colonoscopies. This was later (according to wikipedia) was considered, during the investigation of Wakefield's study, to be "unnecessary invasive medical procedures."

All in all, a very interesting study to read and research the results of.

A Pseudomonas aeruginosa Toxin that Hijacks the Host Ubiquitin Proteolytic System

So this article was pretty cool. It was published in PLoS Pathogens and written by Bomberger et al. So often in people with respiratory infections, the Pseudomonas aeruginosa bacteria can also be found in the lungs of the infected patients. This bacteria secretes a toxin known as Cif. This toxin is known for decreasing the membrane expression of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). CFTR is a giant protein channel that helps in releasing chloride out of the cell. This facilitates in the clearing of mucus from the airways and causing an immune response. The CFTR goes through a recycling process in which it gets tagged with ubiquitin, removed from the membrane, then either A) deubiquitinated and the protein returns to the membrane or B) the protein gets sent to a lysosome and then degraded.

The toxin Cif enters the host cell, and binds to USP10 (this is the protein within the cell which deubiquitinates the CFTR so that it can then be recycled back to the membrane). The binding of USP10 and Cif then disrupts the deubiquitination process so that CFTR remains ubuitinized. This is a very neat mechanism. It seems very simple, all the bacteria needs is to release a chemical, and have it bind within the host cell, and then the host cell is unable to clear the mucus from the airways, and the bacteria retains its nice environment to grow in.

Previously, this group had studied that USP10 deubiquitinates CFTR which decreases the amount of CFTR found in the membrane. They had not studied before how the Cif toxin plays a role in this pathway. I am always amazed at how a research group just whittles away and whittles away until the entire pathway is discovered.

Furthermore, the group showed that with the USP10 protein, it is specifically the Ras-GAP SH3 domain binding protein-1 (G3BP1) that binds in the presence of Cif. The presence of the Cif toxin was shown to both increase the binding of G3BP1 to USP10 and to decrease the interaction between USP10 and CFTR. So the authors not only discovered the pathway, but figured out the specific proteins and domains (at least on the USP10 protein) in which the interactions occur.

The paper had an incredible number of figures, that showed evidence for their conclusions. I thought it was a nicely written paper and that the figure of the mechanism was incredibly helpful.