Questions about the metabolic trap, and some concerns Thanks for the feedback. Is the genetic evidence robust? I'll start with my main concern about the trap, the strength of evidence for a genetic problem. Phair started this work with an intriguing approach of looking for genes where every one of the 20 patients in the study had at least one (predicted) damaged copy and up came IDO2. He then compared the frequency of damaging mutations in the 20 patients with frequency in a much larger reference population, see below: The mutation he focused on was R248W, with a P value of 0.036, just inside the nominal P value of 0.05. However, he looked at multiple mutations, I am pretty sure more than the 5 shown here. And once you start making more than one comparison, you need to adjust P value downwards to correct for the resulting problem of false positives. 0.05 only applies to a single comparison. And 0.036 would not survive any kind of statistical correction for multiple comparisons. That means that the original clue identifying IDO2 doesn't really hold up, which strikes me as a problem. Understanding the biological mechanism that leads to ME/CFS These issues may well have been covered elsewhere, in which case my questions are redundant. Unfortunately, Phair did not have time at Stanford symposium to go into his rationale for how the metabolic trap leads to ME/CFS. 1. Serotonin He briefly discussed that increased (or disturbed) serotonin levels, which he said would result from elevated tryptophan levels caused by the trap, could affect particular nuclei in the brain. These are the Raphé nuclei, which connect to do a whole bunch of other parts of the brain. And it’s possible to explain many of the symptoms of ME/CFS by invoking disturbances to these nuclei, it is not clear why it is the ME/CFS set of symptoms are not whole bunch of other things affected by them (including temperature). But he only had a couple of minutes to explain things and I wondered if he'd expanded on this idea elsewhere? Also, most of the body’s serotonin is in the gut, not in the brain. And @alex3619 has mentioned that IDO is mainly expressed in the immune cells and the liver. Again, has Phair discussed the serotonin issue in more detail elsewhere? 2. Kynurenine Thanks to @Ravn for mentioning the kynurenine issue, where depleted kynurenine might lead to depleted levels of NAD. NAD plays a central role in mitochondrial energy production (as well as being an energy molecule itself, a bit like ATP). 3. Tryptophan Intriguingly, Phair said that his model predicted that trap would last for eight weeks after just 10 days of high tryptophan, and after eight weeks there would be no return. Did he explain how this would happen? It wasn't clear to me from the evidence that was presented. In particular, how would a trigger event such as a severe infection cause the high tryptophan levels needed to prime the trap? Experimental evidence I was impressed that Phair and colleagues had moved rapidly to try to find experimental evidence for the metabolic trap. He presented some very provisional data (for either 3 or 6 patients) supporting the model. 1. Relevant controls Does anyone know how he chose the controls? Surely, proving the trap hypothesis requires controls that have a similar genetic make up patients. The whole idea is that patients have common mutations that put them at risk. But it is not until an unlikely trigger event, such as a prolonged infection, that the trap is sprung. So I think it's necessary to demonstrate a difference from healthy people with a similar level of damaged IDO2 genes – whose tryptophan levels should not have been caught by the metabolic trap. Maybe he is already using such controls: I seem to remember that controls were taken from family members, who presumably have a similar genetic make up. Again, any hard facts on this? 2. Link to serotonin and kynurenine Data was shown for tryptophan and kynurenine, but if the biological effects are mediated result from changes in the levels of serotonin and NAD, we it would help to see data for those molecules as well. Maybe that's part of plan. --- I am thinking of writing to Robert Phair, but I thought I'd ask here first, as I suspect that some of my points have already been addressed.