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Miguel Hernán Profile picture
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Apr 13 • 8 tweets • 5 min read
1/
 Our findings on a fourth dose (2nd booster) of the Pfizer-BioNTech #COVID19 vaccine are now published.

Compared with 3 doses only, a fourth dose had 68% effectiveness against COVID-19 hospitalization during the Omicron era in persons over 60 years of age.

Interestingly...
2/
 ... this is yet another example of the need for good #observational studies that emulate a #TargetTrial.

Would it be better to have a real randomized trial? Yes

Do we have a randomized trial? No

Will we have a randomized trial? Perhaps, but too late for a timely decision.
3/
 Last year, observational evidence was also used to recommend a first vaccine booster.

Our and others' studies provided evidence on the booster's protection against hospitalization after infection with Delta:


Policy makers listened. Lives were saved...
4/
 5 months later, our results for Delta were confirmed by a real randomized trial, but this trial

couldn't estimate effectiveness for hospitalization (10,000 people vs 1.4M in observational study)

reported its findings after Delta was gone

So can we please stop the debate...
5/
 ... about whether observational studies can be used for #causalinference?

They ARE used for causal inference. They have guided vaccination policy. They haven't been terribly wrong.

How can some journals justify a ban on explicitly causal language? 🤯
6/
 Let’s move beyond the dichotomy of randomized trials VERSUS observational studies for #causalinference.

Randomized trials and observational emulations of target trials are complementary approaches to causal inference.

I give examples in this thread👇
7/
 .. and in this one👇


We need explicit recognition of causal goals in observational emulations of target trials.

This idea shouldn't be controversial: we're already using observational data to guide policy.

Let’s just keep doing it after the pandemic.
8/
 Besides high-quality observational data & sound #causalinference methods, target trial emulation requires good scientists.

Many thanks to my colleagues Ori Magen, @RanBalicer, Noa Dagan et al @ClalitResearch + Ben Reis, @mlipsitch @HarvardEpi. What a treat working with them.

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More from @_MiguelHernan

Miguel Hernán Profile picture
Dec 3, 2021
1/
 We emulated a target trial of two #COVID19 mRNA vaccines in the largest healthcare system in the US.

Both vaccines were similarly effective, with Moderna slightly better than Pfizer-BioNTech.

But that isn't the most important conclusion of our study.

2/
 Spring of 2020: #COVID19 vaccines are developed.

October 2020: Results from randomized trial are announced.
businesswire.com/news/home/2021…

~6 months from development to evaluation of effectiveness.

Utterly impressive. Unprecedented.

Kudos to the pharmaceutical industry.

Now...
3/
 December 2020: Vaccines become available.

December 2021: Where are the big randomized trials for COMPARATIVE effectiveness?

1 year, still *crickets*

Billions of taxpayer dollars and we don’t get to know which vaccine is better and safer?

Not so impressive, pharma industry.
Read 6 tweets
Miguel Hernán Profile picture
Aug 25, 2021
1/
 Vaccine safety: We compared excess adverse events after #COVID19 vaccination (Pfizer-BioNTech) and after documented #SARSCoV2 infection.

nejm.org/doi/full/10.10…

Take-home message: Low excess risk of adverse events after vaccination, higher after infection.

Some thoughts👇
2/
 Preferring #SARSCoV2 infection over vaccination has become even harder. (Remember: infection also increases the risk of severe disease/death)

This is a good illustration of how #randomized trials and #observational studies complement each other for better #causalinference...
3/
 The original #randomized trial estimated vaccine effectiveness to prevent symptomatic infection, but was too small to quantify vaccine safety.

That's what #observational studies do.

Now a different sort of question: Why could we do this study in the first place?

2 reasons.
Read 8 tweets
Miguel Hernán Profile picture
Mar 18, 2021
1/

Many countries are vaccinating their elderly. Can we relax control measures now?

No.

Even with 50% of elderly vaccinated, uncontrolled #SARSCOV2 transmission may overrun the healthcare system.

We explain @AMJPublicHealth today, led by @_gmales
ajph.aphapublications.org/doi/10.2105/AJ…
2/
Data from Madrid, Spring 2020:

Critical care requirements peaked at 5 times the usual capacity.

Hospitals managed to increase ICU capacity by 3-fold.

Heroic but, sadly, insufficient.

The healthcare system collapsed. Not everybody who needed critical care received it.
3/
If 50% of the elderly had been vaccinated, critical care requirements still would have peaked at almost 4 times the usual capacity.

Greater than the ICU capacity of any country in the world.

Only a prolonged lockdown could return ICU requirements to normal.

One last thing:
Read 4 tweets
Miguel Hernán Profile picture
Mar 12, 2021
@ProfMattFox 1/
The odds ratio from a case-control study is an unbiased estimator of the

a. odds ratio in the underlying cohort when we sample controls among non-cases

b. rate ratio in the underlying cohort when we use with incidence density sampling

No rare outcome assumption required.
@ProfMattFox 2/
Because the odds ratio is approximately equal to the risk ratio when the outcome is rare, the odds ratio from a case-control study approximates the risk ratio in the underlying cohort when we sample controls among non-cases and the outcome is rare.

But...
@ProfMattFox 3/
... for an unbiased estimator of the risk ratio (regardless of the outcome being rare), we need a case-base design, not a classical case-control design.

Of course, all of the above only applies to time-fixed treatments or exposures.

As for the causal interpretation...
Read 5 tweets
Miguel Hernán Profile picture
Mar 5, 2021
1/
 We recently confirmed the effectiveness of the Pfizer-BioNTech vaccine outside of randomized trials @NEJM.
nejm.org/doi/full/10.10…

Studies like ours are being used to promote a vaccine passport to travel in the US, UK, and European Union.

A few clarifications are in order.
2/
Before we start, a disclaimer:

Vaccine passports involve complex ethical, economic, and political considerations.

Here I talk exclusively about scientific issues. The goal is that those making decisions have a better understanding of what we do and do not know as of today.
3/
 Based on our study, we can say confidently that the vaccine is highly effective in preventing you from getting sick with #COVID19.

Based on our study, we can't say confidently that the vaccine is highly effective in preventing you from getting infected and infecting others.
Read 9 tweets
Miguel Hernán Profile picture
Feb 24, 2021
1/
 We've just confirmed the effectiveness of the Pfizer-BioNTech vaccine outside of randomized trials.

Details @NEJM: nejm.org/doi/full/10.10…

Yes, great news, but let's talk about methodological issues that arise when using #observational data to estimate vaccine effectiveness.
2/
 A critical concern in observational studies of vaccine effectiveness is #confounding:

Suppose that people who get vaccinated have, on average, a lower risk of infection/disease than those who don't get vaccinated.

Then, even if the vaccine were useless, it'd look beneficial.
3/
 To adjust for confounding:

We start by identifying potential confounders.

For example: Age
(vaccination campaigns prioritize older people and older people are more likely to develop severe disease)

Then we choose a valid adjustment method. In our paper, we matched on age.
Read 12 tweets

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