Weāre getting in the weeds now. But sure, why not?
Iāve read Nassim Taleb on randomness in my early 20s and more lately Stephen Wolfram on computational irreducibility and the like, so the weeds are familiar territory, but I donāt want to merely rehash other peopleās thoughts.
I meant the word ālikelihoodā to loosely mean, āepistemic confidence.ā We make decisions in the absence of perfect knowledge ALL the time. I donāt mean that if we keep rolling the dice on the hypothetical perfect, decades long RCT on ezetimibe vs. Alzheimerās we will get different outcomes in different branches on the multiverse. Indeed, it either works or it doesnāt, but we donāt know which, and in the absence of clarity on that issue we can presume the outcome, to be positive or negative, for the intents and purposes of taking vs. not taking that drug with Alzheimerās protection in mind, and do so using proxies to the actual knowledge which we lack. Those proxies can be a consideration of the side effect profile of the drug.
Say, assuming that it does diddly for Alzheimerās, will it be much worse than placebo, can it hurt? From what I understand of it, itās highly unlikely to harm any individual. And here āunlikelyā is used in the probabilistic sense, when we use it in general, even though my own specific biology is deterministic as I am not an average of all gene variants and phenotypes of humankind, I am a unique human female, of a unique molecular composition, and Zeta will either not cause me side effects or it will. At any rate theyāre presumably easy to detect and reversible. Even better, it has positive effects on lipids and since Iām apoE4 that should be my choice of intervention anyway for lipid optimization, in preference to a statin.
So thatās my intellectual liverās āfirst passā metabolism of risk analysis. But if the risk profile is concerning, I proceed no further.
Next, I look at the data at hand. Was the observational study well conducted? To be honest I grow lazier and lazier every year and outsource much of the nit picking to this group. If there was something truly wrong with it Iād expect @adssx or someone of his caliber and obsession with detail to point it out.
Next, I look at the effect size. p-values are one thing but I donāt live and die by them. More important, presuming for the sake of argument that the drug DOES have an effect, is it going to make a true difference or be a rounding error? In this case there seems to be a massive effect size. Thatās encouraging.
Last, I look at plausible mechanisms of action. And I say PLAUSIBLE. If zeta did cross the BBB then Iād look little further and presume it did something in the brain. Suppose it doesnāt cross it? Well, first Iād take that with a grain of salt, as our knowledge of whether it does or doesnāt is imperfect and can be further enlarged. But even if I take for granted that it doesnāt, there are other ways it can nonetheless POTENTIALLY exert influence on the brain, some of them Iāve already touched on in principle. And I go back to my being a unique individual ā I have apoE4 which is known to cause a leaky BBB, so maybe zeta barely crosses the average personās BBB while having substantial penetration into MY BBB.
At any rate, I have to remember that I cannot, through didactic logic, arrive at any hard and fast conclusions here, because thereās so much about human physiology that we wonāt understand. Thereās unknown unknowns there, that should be accepted as a given and give us all a modicum of epistemic modesty when we approach these things. I donāt expect the solution to Alzheimerās to be anything obvious. If it were it would have been found already. And we canāt be overly reliant on mechanisms of action, since we donāt even fully understand its pathology. Recall if you please how a dogmatic adherence to certainty vis-Ć -vis its source (amyloid plaque and tau protein) ended up leading researchers astray for decades, spinning their wheels. I donāt even fully understand HOW it is that apoE4 confers higher risk. I see hints at multiple mechanisms but no smoking gun. And Iāve read about this extensively as it honestly freaks me out and keeps me up at night if anything does.
Soā¦ am I taking zeta?
No. Iām nursing a baby and if I apply my loose āalgorithmā of risk analysis to her wellbeing itās āunlikelyā to be a wise choice until sheās weaned. Again, it might be totally fine and in fact it either is or isnāt. Itās a deterministic outcome. But I donāt know it. Iām erring on the side of doing no harm.
When sheās weaned I will get on it for sure.
