I have read through this observational data emulated target trial and would be interested in what the methodologists here think of the study. I personally like it and only found small quibbles with it. I think the conclusion is right and I suspect it will bear out in the prospective trials that are currently running with HCQ not showing any benefit in the end. In this article, it seems like the authors were pretty careful about how they set their analysis up.
Thanks!
I was going through posts on target trial emulation and thought I should flag that this was not a target trial emulation. It was called that on the preprint but on eventual publication in the BMJ “target trial emulation” was dropped from the title. We have a preprint that explains what a target trial emulation is, and by extension, what is not and uses a clear example of the Stanford Heart Transplant Study.
Moved to another discussion.
The main aim of the post was to call out the target trial issue and I think we should stick with that in this thread. Interestingly, these authors allowed a “grace period” of 48 hours after admission for initiation of hydroxychloroquine (HCQ) but the start of follow-up (baseline or time zero) for each patient was the time of admission to hospital. This leads to what is called a “from threshold” analysis (the threshold being hospital admission) which is also the eligibility. We call this a type 3 failure of emulation where the treated are immortal till they get HCQ while the controls could die within this 48h period. Additionally there were people who received HCQ after 48h and these were excluded which is again a problem and they dealt with this by two sensitivity analyses: “Firstly, mimicking an intention-to-treat analysis: all patients eligible for the study were analysed, and those who received hydroxychloroquine after 48 hours were analysed in the control group. Secondly, mimicking an as-treated analysis: patients who received hydroxychloroquine after 48 hours were analysed in the treatment group.” This again is incorrect so there were many issues here of failure to emulate a target trial and your comments on this aspect would be appreciated. You can move the other comment on pathways to our previous thread so that more discussion on that aspect may ensue.
Brilliant point that eligibility and time zero are the “natural pair”. Indeed that the natural pair is actually biological state and biological time, with eligibility and time zero serving only as observable proxies.
Minimum requirement (target-trial framework)
T0 = E
Everyone becomes eligible and enters follow-up at the same procedural time.
This requirement addresses temporal biases arising from misalignment of eligibility and follow-up. It is fundamentally an administrative or methodological requirement rather than a biological one.
Stronger requirement
T0 = E = B
where (B) is a biologically meaningful state.
Under this framework, eligibility and follow-up begin at a biologically relevant point rather than at an administrative event. Merely synchronizing on a procedural clock does not guarantee biological coherence. For example, a 48-hour grace period represents approximately two rotations of the Earth. This interval is defined by convention rather than by disease biology.
In rapidly evolving infections, such delays cannot automatically be regarded as trivial administrative accommodations. In our studies of Ebola viral load and antibody time series, substantial biological evolution occurred over comparable periods. Viral replication, host immune activation, and tissue injury may change markedly during such intervals. A synchronization point defined solely by elapsed clock time therefore risks grouping together patients occupying very different biological states.
Strongest requirement
T0 = E = B(t)
where eligibility and follow-up are synchronized not only on the same biological process but also on approximately the same biological time within that process.
Under this formulation, patients are aligned not merely because they share a diagnosis or biological pathway, but because they occupy comparable positions along the trajectory of that pathway. Two patients with the same infection may differ substantially in biological time despite sharing the same hospital admission date, positive test date, or severity threshold.
Achieving this level of synchronization may require analysis of relational biological time series, including pathogen burden, immune response trajectories, biomarker evolution, physiological adaptation, and other dynamic features that more faithfully represent progression through the disease process than calendar time alone.
The progression from:
T0 = E.
to
T0 = E = B
to
T0 = E = B(t)
represents a shift from procedural validity, to biological validity, to biological-temporal validity.
I agree, B(t) is important. To align B(t) with T0=E means that “severity” at say admission needs to be accounted for and thus I would consider B(t) a confounder (and we can adjust if there is a measurable marker for B(t) at baseline). However if A happens at variable times post admission in only the treated group, no direct adjustment is possible to align A and that is where the difficulty arises.