The Petty/Bone RCT

[llynn]

@Elias_Eythorsson

Can we have an honest discussion about what inclusion criteria would look like in a critical care trial for severe acute pathology that avoids the pitfalls of “petty/bone”? Let us start with a specific example to help my understanding, what are your thoughts about the recently published BALANCE trial .

Absolutely and I certainly hope you are willing to do so. Let’s contrast the above aspirin for sepsis trial with the BALANCE trial and then discuss how to avoid the pitfall of the PettyBone RCT mod.

Note the the Aspirin for Sepsis Trial (PettyBone) RCT uses a first triage non-disease specific threshold set of SOFA to capture a second set of different diseases (which are lumped as the synthetic syndrome of “Sepsis”) and then Aspirin is tested using this PettyBone RCT mod. purporting to generate a **single average treatment effect (ATE) of aspirin on this second set of different diseases. (This is generally the way that sepsis and ARDS RCT have been done for 36 years, since Bone’s failed methylprednisolone for SIRS trial in 1989. They have not been reproducible.)

• 1. “Sepsis was defined according to the Sepsis-3 definition by the presence of a suspected or confirmed infection and an increase in the SOFA score of two points or more.”…
• 2. “Patients in the ASA group received 200 mg orally or enterally once a day for 7 days, regardless of ICU discharge.”

Contrast that to the BALANCE trial

• "1. Patients were eligible for enrollment if they were admitted to a participating hospital at the time a blood culture was reported as positive with a pathogenic bacterium…A full list of inclusion and exclusion criteria is provided in Table S2.…

• 2. Adequate was defined as antibiotic therapy to which the organism was susceptible according to local laboratory reports;"

Not not only was there an objective diagnosis in the BALANCE (bacteremia) but the treatment was specific to the diagnosis.

So the pitfall is avoided by having a diagnosis or specific measurable targetable homogenous thread in all the patients in the RCT. A set of non-disease specific thresholds, such as SIRS, Sepsis 3 (which is SOFA), or the next threshold set generated by the next Sepsis or ARDS consensus task forces simply cannot do that.

One could argue that BALANCE should have separated the organisms and performed a separate RCT on each and this would have been more in keeping with Bradford Hill’s method. Certainly they had 74 centers so this would have been preferred. As it is we are left wondering if certain more resistant pathogens might not fall within the ATE. In a sense n is artificially high for each specific organism. Yet this RCT mod is profoundly better than a PettyBone RCT mod.

Great to have a discussion. How do you perceive these two RCT mods in comparison with Bradford Hill’s and Fisher’s teachings? Do you agree with my analysis here? What are your views or the next step? Do you think that lumping by non-disease specific threshold set might eventually reveal a common thread?

I look forward to the discussion. I hope others will also contribute.

[Lawrence_Lynn]

@Elias_Eythorsson

Can we have an honest discussion about what inclusion criteria would look like in a critical care trial for severe acute pathology that avoids the pitfalls of “petty/bone”?

@Elias_Eythorsson

Just sending this in case you missed my response to your request for an honest discussion of the comparison of the PettyBone RCT and the Balance trial.

I think many are looking forward to your response and thoughts as this is a very timely and popular thread and topic.

[Lawrence_Lynn]

Corrected reply above should be to @Elias_Eythorsson

[Lawrence_Lynn]

I don’t think @Elias_Eythorsson is coming back for that “honest discussion” since it’s been over 3 weeks but maybe he will. @ESMD and @Doc_Ed both denigrated and summarily bolted. That was not surprising.

I will summarize this thread:

First: By deep review of the history, I identified the 1967 and 1989 combined apical error of a pathological science. This error was the RCT modification called the PettyBone RCT which eliminated the need to diagnose a disease and replaced the diagnostic process with a first set of guessed thresholds to lump (by triage), a second set of different diseases for this new modified RCT.

Second: I showed that this RCT mod is pathological science which has not rendered reproducibly positive results for 35 years despite hundreds of such RCT. Furthermore a one-size-fits-all standard ventilator protocol based on this pathological science caused great harm during the pandemic. This protocol has been abandoned.

This proved that pathological medical science is not only wasteful of money and careers but is harmful to the public.

In any other industry the discovery of a fixable apical error would be an exciting revelation causing action for reform. I was the first to discover that the specific source of the lack of reproducibility of critical care RCT was the modification of the Bradford Hill methodology and, even if unrecognized now, this was a great discovery for the science of critical care.

Indeed critical care scientists have long blamed raw generalized heterogeneity for the failure but failed to go back in history to seek the source. For this reason they failed to see that thier past leaders Petty and Bone had integrated profound heterogeneity into their modified RCT methodology itself by lumping different diseases using a guessed threshold set as triage.

Massive excitement would have been generated in industry responsive to the discovery of a fundamental methodological cause of decades of waste and failure because it would be seen as an amazing opportunity for a new direction and greater productivity.

My father, a chemical engineer in the 1950s, discovered a source of waste in the processing of aluminum. His work was hailed.

In contrast, my discovery of a fixable, apical source of waste in medical science triggered insults and denigration. No one argued it was not pathological science (they could not). Rather they simply did not like the promulgation of it.

I recall this same thing happened to a prominent thought leader (who later was president of the ACCP). She presented evidence over a decade ago at a national meeting that the AHi was not a gold standard for severity of sleep apnea. Rather than being praised for her work and insight, she was accused from the lectern of “euthanizing children”. This public denigration, of course, was said as “tongue in cheek” but it was also a shot across the bow warning her not to disrupt the flow of the spice.

Likewise the denigrating response in this thread to my discovery of the historical onset and source of decades of waste as a function pathological modification of RCT methodology shows that scientists cannot be trusted to police themselves just as they could not be trusted to police the severity standard for sleep apnea.

Any challenge to deep decades old dogma which is rendering a river of grants Is perceived as a challenge to “mother science”. This is why they become verbally denigrating and then quickly run away.

It’s fine to end this thread now but the results of this experiment have made me realize that the “threshold set guessing task forces” must be defunded by the new NIH.

We must cut off the source of the PettyBone RCT mod. or they will simply stay the course.

Without the first guessed threshold set (which , believe it or not, the task force reconvenes to guess anew every decade) this pathological RCT mod will collapse because they won’t have a standard means to triage the patients (to lump the different diseases) for the RCT. They must then turn to the teachings of Bradford Hill and study each disease separately or find a homogeneous thread to identify those included. At the same time the NIH defunds the threshold guessing task forces, the NIH should liberally fund the reform.

Unless anyone has a prolog, goodby all.

This social experiment was fully supportive of my original hypothesis which states:

Scientists will generally seek to discredit any effort which impedes a well established flow of grant funding without regard to the merit of the research.

[f2harrell]

To reiterate something I said earlier, let’s move towards continuing the discussion with an emphasis on designing future trials.