So could you just start by saying your name and what your current position is?
Yes. So my name is Daniel Alhambra, and I am a professor of pharmaco and device epidemiology here at Oxford.
I lead a group of people. It's a section called Health Data Sciences.
So we basically use have data to produce knowledge and to, you know, try and improve human health.
Hmm. Well, we're going to talk about that a lot more. But first, before that, I'd just like a little bit more about your background.
So how did you first get interested in science and into this interesting branch of science, which, to be honest, I hadn't really come across before.
Yes. So I am a medical doctor by training, so I trained as a as a GP.
I practice as a GP for a while and then I kind of realised that, you know,
there's a lot of uncertainty in how we manage disease in primary care and also I would say beyond primary care.
So I started doing see into research methods, epidemiology studies, just to learn the basics of how we, we handle data to generate knowledge.
So I did the first one was I did it in Spain where I'm from in Barcelona.
And then after that I started my Ph.D. and as part of that, I,
I had the fortune to spend a little bit more than a year here at Oxford as a visiting student.
Right. And that was that was basically a project using existing data, routinely collected data, electronic medical records and the like,
from Spain and from the UK to look at a number of musculoskeletal conditions like arthritis,
basically, and also fractures and bone fragility problems.
So yeah, basically, you know, through that kind of route, I ended up finding my passion with small to generate data,
them to consume data as a clinician, thus in their day to day job.
And although I have been practising as a as a physician until very recently, basically I believe that I am,
you know, much better at doing research than not practising as a clinician.
And that's that's where I'm headed. So this is I mean, this is where I think it's really interesting.
This is so, you know, everybody knows about clinical trials where you, you take a treatment or a device and you test it on the population.
Yeah, Prospectively, what you're doing is looking at people who are going through the health care
system and using the data on that that shows what drugs they've had and so on,
analysing that retrospectively to try and come up with answers.
How do I can you give me some idea of the relative and importance of both those two ways of doing things?
Yes. So I think unfortunately there's a little bit of a division in how people see this sometimes.
You know, one is good data, the other is bad data. I think they are very complimentary.
Actually.
The the beauty of clinical trials, of course, is that you have very clean data on whatever outcome or whatever condition you want to look at.
So you collect the information you need and you want.
And additionally you also have the beauty that you are randomising people to receive a treatment or not,
meaning that in the end the treated and untreated groups are comparable and they are basically
the same on everything you want to compare them except the treatment they received.
And therefore any differences in outcomes you know can be referred to the treatment they receive right in the data we use.
That doesn't happen. We look at data as it comes from clinical practice, from routine practice that has limitations,
including the fact that people tend to take treatment for a reason.
So those people are not necessarily comparable to the people who live and receive the same treatment.
That's what we usually call confounding.
But also it has other limitations, including the fact that we use data that was collected in not always ideal conditions.
Right? So, you know, you can imagine in GP practice when things are busy, potentially people will be called things more quickly and less accurately.
So there's a lot of work that needs to be done on kind of curating that data before you can use it for research.
Now, the advantages of this kind of data that I don't think are, you know,
preferable to trial data that are complementary are first that this kind of data includes,
of course, anyone who goes through the health care system here in the NHS, even more so because it's a kind of universal system, right?
So you see basically people that have been excluded from trial participation for whatever reason,
including co-morbidities sometimes, or because they have a shorter life span or because they are pregnant,
pregnant or, or very young, all those people, when exposed to a treatment,
will turn up in our data so we can collect information on what happened to them without exposing them to a risk.
Unless that happened because it was considered necessary through routine clinical practice.
That's one key advantage, I believe, to more care than. It is.
First, The size of the data I can get hold of is, you know, an order of magnitude bigger.
Right.
And that, of course, you know, in some situations it matters, especially when we're looking at safety outcomes that tend to be, of course, rare.
We do need big numbers. And I think, of course, I think a very relevant example is the COVID vaccine site, where we'll get we'll get to that.
So I think that's a very good general principle. Yeah, that's a very good example.
And then the final the final one that I think is not only the number of people,
but also the possibility to follow them up for much longer than a trial.
That's right. So a trial costs a lot of money. You follow people up for a certain time,
but then you basically let go in this kind of data because the data is generated as people go through the health care system,
you can follow people up for as long as they were registered in the GP practice or or for as long as they were having contact with the NHS.
So that can be sometimes ten, 20 years of data available.
Now you've mentioned you use both UK data and Spanish data and perhaps as elsewhere in the world now, and you also used the word cure rate earlier.
So who, who creates these databases and how, how can you ensure consistency across different databases?
That's a very good question. So yeah, indeed.
So we have used data for many different topics, but very, very specially very specifically for COVID from many different parts of the world.
Let's not talk about it just yet. So, yes, so that data is typically initially pseudonyms, you know, for for kind of governance reasons.
The data is it has a fast kind of process that's done by the data you can call it.
Then, though, they three words depending on the country, they use different terminology.
Right. But it's basically the people who made the data available to researchers.
And then these tend to be private companies or are they government based?
So in the UK, in Europe, mostly government based, in the US, mostly private companies and then other parts of the world, it depends on the country.
But I would say in Asia I use some Asian data and with the exception of China,
most of the other countries would be selling or, you know, making the data available through private routes.
But in Europe, it's typically government based institutions or trusted third parties, as they call them, right?
Yeah. So so that's the first process.
The second process is, of course, once you receive the data, you need to do all the checks to make sure that the data is fit for purpose,
that you can use them, that it's got quality completeness and all that.
Typically that will be done by my team if I am directly accessing the data and we do that for data that we've been using for many years,
including for instance, data from Spain or from the UK. Now, the third step in the process that you mentioned already is this interoperability, right?
So making data basically similar across the world.
So you can do international collaboration when that is needed or when that is desirable.
And that is something we've done a lot of work on recently. In the last three, five years.
This was just pure chance or serendipity.
I don't know. You know, just when the pandemic hit, we were already working on this topic of making data look the same across the globe,
because all these data sets in a way contain similar information, right?
It's going to be, you know, your social demographics, what conditions you have,
what medicines you're taking, all that, but maybe recorded in different languages, in different systems.
The format of the data is most likely going to be different as well.
So there is this process of what we call mapping to our common data model,
such a common strand structure or format, which then enables international collaboration without moving data.
So I can analyse data from the UK that I have mapped to this common data model.
In this case we use our common data up and then basically if I have a collaborator in, say, Spain or in South Korea that has data in the same format,
I can share my code and that code should run in their data and then all they can or have to share is results.
Really so aggregated data, we don't move patient level data anymore.
And that has many advantages in terms of, you know, information, governance and security, because you keep the data where it is.
You just you know, you have this version of the data that has been formatted in a very specific way and then we can analyse it,
what we go in a federated manner.
So we basically have someone writing the analytical code and then colleagues or collaborators running that code across the globe.
Mm hmm. So you talk about size, the size of study, typically how many patients are represented in the kind of study you might do so.
For the pandemic. We will be talking typically of tens of thousands of people.
That was the usual. Nowadays, Yeah.
Millions sometimes. Hmm. That's extraordinary.
And before we get to code, we're going to get it in just a minute.
But can you give me a couple of examples of the kind of question that you might have been asking?
No, it is also not related to Katrina, Not least not yet.
Yes. So let's go. I'll give you an example.
Pre-pandemic and post-pandemic not related to COVID.
So an example of something we were doing before the pandemic was looking at and this is NIH funded research that funds,
I felt, a senior fellowship that I that I do a deal for myself.
So we are looking at whether in very old and very elderly people who have lots of conditions,
there's always this question on whether it's worth it's considering at least stopping some of the
treatments they are taking because they are deemed to be unsafe and maybe not that useful for them.
And an example of that could be statins, for instance.
Right. So this is a question that is very tricky to investigate in a trial because you have these people
who are taking the treatment and you have to randomise them to stop taking the treatment or not.
And that's not something that, you know, is easy to to convince people to do.
Right. So we we were looking into that specific question of what happens when you stop one such treatment, what we call preventative therapies.
You know, and in the real world, some doctors might simply decide not to make that change.
And ideally, you know, it's it's kind of an ideal scenario because there's so much uncertainty.
That is it is to be expected in that way that those decisions are small and random.
Right. If you had very clear knowledge that, let's say, stopping therapies causes harm or it doesn't,
then you can expect that everybody would be doing the same. But when you have these situations where you don't have very good evidence,
there's more randomness in those decisions and you can leverage that to do this kind of observational research.
That's an example pre-pandemic post post-pandemic we are doing. And what was the outcome?
Right. So that's something we we we are still working on right now because, yeah, we could talk about priorities, right?
So, you know, that was deprioritized.
It's looking like like if you stop these therapies, you need to be careful because at least for some time after stopping them,
there's going to be an increased risk of the events you were trying to prevent.
So studying, for instance, will be heart attacks, you know, But that's that's something we are writing up now as we speak now.
A post-pandemic example would be a lot of what we're doing on cancer.
So looking at, you know,
different presentations of different types of cancer and the prognosis of cancer and then what does that look like before and after the pandemic.
So that sort of observational study looking at prognosis and and presentation of cancer,
different types of cancer in the population and across Europe in this case.
And you mentioned risks earlier.
So, you know, is that that that just these two main questions you're asking, does this treatment work, this struggle, this device work?
And also, does this treatment or device do harm? Those are the two kinds of big questions like asking, was that it?
I think this three types of research we do with this kind of big data,
because data one indeed is looking at the effects of medical devices, procedures on the treatment medicines.
And you can look at benefits and you can look at risks. Typically,
we do more of the risk bit of the picture because that's what's harder to do with
trial data because these are rare outcomes for the reasons we discussed earlier.
Right. But but we have done also some work on benefits and that's published work.
Now on on top of that, the other two types of studies that we do a lot of one is basic epidemiology.
So characterising a condition, how often does this happen in a population?
In the example I was mentioning, are we seeing, for instance, an increase in the incidence of particular cancer in younger people,
which we will be worried about that sort of thing that we call characterisation or descriptive analysis.
And the third type is what we call prediction.
So this is where we take a group of people and say what happens to people when they get diagnosed with osteoarthritis?
What are the people who are at the highest risk of having a knee replacement or one
of the people who are at the highest risk of falling and having a hip fracture?
So that would be prediction. Prediction work. Mm hmm.
Very interesting. Right. We'll get to Kevin now.
So can you remember where you were or under what circumstances you first heard that something was going on in in China?
And how soon did you realise that that was going to fall into your area of interest?
Yeah. So. So back in December 2019, we were hearing the news, right?
It wasn't very. Solid data yet. So it was very hard to really figure out what was coming.
But yeah, as an epidemiologist, I was kind of, you know, already paying attention to the to the information we were getting in January.
It was already very obvious that this was coming. You know, we were seeing images in China, you know, lockdowns, and we knew that there were still,
you know, planes flying people around the entire world pretty much.
Right. And you were here in Oxford, but I forgot to pick you up on your career steps.
So. No, no, no. I've been here continuously since 2012.
Right. So, yeah, I guess between December and January that year, I still went to Spain for the Christmas May.
That year I managed to get the budget, let's say from January.
I was here in January already.
So there was a possibility that we might be able to contribute some work because of these collaborations that we have internationally.
And I was very, very busy because we had we were due to host a UN international conference, my group and I here at Oxford,
where of course I was in touch with all these colleagues from, for instance,
China or South Korea who were saying we might not be able to trust this event happen.
So which month with it meant to happen in March. So that was due to have it on the 20th of March.
So so yeah, at that time already, you know, we were concerned, but yeah,
it wasn't clear whether we would have cases, although, you know, we could see it coming.
Right. So we were already looking into what happened.
If we cancel, you know, we lose all the money and that kind of thinking of preparing for the worst.
So that was January. And then in February it was already very obvious that we had to cancel the conference.
You know, the minute we saw what was happening in Italy and in Spain.
And, you know, we have colleagues there who were working in in the hospitals and telling us what was happening.
And so Spain, I mean, we we had a lot Italy was very high profile, but I don't remember very much about Spain.
But did they also have a problem before it came to UK?
So happens. So Italy and Spain are very connected countries.
Yeah. Because they are. Yeah. They speak very similar languages and there's a lot of mobility between both countries.
So the minute it started getting a little bit better for that first wave in Italy, it started getting really bad.
In Spain, especially in big cities like Madrid and Barcelona. I think the first recognised case is 23rd, 24th of February in Spain,
but here like a week later, they were already, you know, thinking of locking down and so on.
So it was, yeah, maybe a couple of weeks earlier than the UK when things had to be done very rapidly.
And at that point, you know, it was very obvious to us who were talking to these people all the time.
And I was also talking to people in Asia that there was no way we were going to do it.
So I guess that's that's the summary of those first few weeks.
And I mean, one of the first responses or a fairly early response was the idea of trialling repurposed drugs.
Was that something that you felt you could contribute to in your approach?
Yes. So so at that time, already in late February, we decided we had to cancel that conference I mentioned and we decided that instead of doing that,
we would have something that we're very used to now.
But at the time sounded quite novel, a kind of virtual we called it study athon,
which was basically let's gather all our colleagues internationally and hold.
I think it was a four day, you know, 24 seven activity because of course you could have people awake during the whole day looking
at a number of things and the number of things we we and this was all on an online screen.
Online. Yes, yes, yes. On teams, which at the time was, you know, something we had not used that much.
So we basically, you know, all the people who had registered for this conference, we had to tell them we're going to cancel.
And then we opened, you know, we told all of them, if you want,
we are going to be hosting this event that's going to be online and we're going to be working on research.
Right. And meeting and discussing other things, which was the plan originally.
And it was very nice to see. Of course, you know, all these collaborators from around the world rallying together.
This was a with a community called Odyssey Observational Data Sciences and Informatics,
or DSA, where, you know, we were going to host the Odyssey Europe meeting.
And and these colleagues, you know, from all over the world said, Yeah, let's work together on this.
And then, you know, late February we were writing on writing the protocols on the studies we wanted to do,
and the most important ones were, first, really characterising the condition because there was a lot of uncertainty.
You would remember some people were saying this is like the flu, and we published What If He's a seminal paper?
The first international characterisation of the condition,
looking at people hospitalised with COVID versus people hospitalised with the flu in previous years just to show.
Differences, Right? We can get into a little if you want, but that was a very important piece of work.
Second piece of work was looking at repurposed medicines or medicines people were
talking about because at the beginning we didn't have a lot of data on COVID patients.
We were interested to learn on medicines that were heavily used, but maybe we didn't know so much about in terms of safety,
because, again, you know, some of these medicines have been I'm talking now hydroxychloroquine in particular.
And we wrote a paper looking at some concerns with the use of hydroxychloroquine in combination with antibiotics,
which is, again, another advantage of this data is that you see everything that happened,
right, is not like a trial where you have one treatment only here, if someone is taking two or three, you see them in combination.
And we found a very strong signal for a cardiovascular safety risk when people combined hydroxychloroquine with azithromycin,
which is an antibiotic that was being heavily used at the time, and this made it all the way to the regulators nationally and internationally.
There were changes in clinical guidelines, change changes or, you know, letters and talking each and say don't combine these two treatments.
And that was using not really using COVID patient data.
This was using retrospective data that we had risk. Yes, but there was indeed a plan then also to look at ones.
We had more data on COVID patients, look at whether the treatments also had any benefits.
Right. Because that was, of course, an important consideration.
You need to balance risk and benefit.
And the last bit of work was trying to identify who was a very high risk of getting, you know, severe COVID when they got the infection.
Right. And that that's again, information we produced and we shared what here nationally with with Sage and and the advice of the government,
but also internationally when everybody was interested because we found that it was
relatively straightforward to predict who was going to get in trouble based on,
you know, five, six conditions, age and sex, as we probably know very well known.
But at the time, that was a big question. And then did ethnicity come up it in that?
So ethnicity didn't come up in that first bit of work,
probably because we were mostly relying on data from countries where there's not a lot of variation in ethnicity.
But we had data at the time from South Korea and Spain, I think I say, and while Spain has some more variation,
but probably not for the ethnicities that lead to a high risk of of severe COVID and South Korea has very little ethnic collaboration.
So we didn't see it at the time, but we still saw that we could predict very accurately who would get severe COVID based on five, six, seven features.
You could basically create a very simple, you know, equation and calculate.
So things like age and age six obesity, diabetes, cancer, hypertension.
I think that was one of the needs.
And and was there any overlap between or relationship between what you were able to do with databases and what the recovery trial was doing,
which was a prospective trial of treatments? Yes.
So I think I think hydroxychloroquine is a beautiful example.
We we did observe and this was already made available to key stakeholders in during that first week that we work together with colleagues.
So late March, very early April, we wrote already the manuscript with these findings that were very important and and I
think so that showed that hydroxychloroquine was not necessarily as safe as we thought.
And especially when you combine that with these antibiotics and, you know,
people are using these combinations very often just to protect against bacterial pneumonia and there was a lot of uncertainty.
So if you remember then in June, recovery showed that the treatment was also not effective.
So we knew by June with two seminal papers from Oxford that hydroxychloroquine wasn't
a good idea because it wasn't as safe as we thought and also it wasn't converted.
Yeah, I think it's a perfect example of complementary information coming from these two types of data.
Yeah, and I think that was beautiful to observe how these different studies can complement each other.
And I mean, similarly dexamethasone, which turned out to be of benefit, was that something that you were looking at in the data?
So for Sun at that time, we were not looking at that because there wasn't a lot of use of steroids.
I don't know if you remember, but there was a lot of, well, colleagues because again, we had a lot of data from Asia at the time.
The thing is, from the experience that colleagues from China and South Korea had from us,
one, so, you know, 20 years before they thought that steroids were not a very good.
Then for this condition and they were not using. It is quite interesting how these things, you know, basically.
So without I guess with without recovery,
we would probably have never recommended this treatment because previous similar conditions taught had told us not to use them.
Right. So it's great that that recovery happened and we managed to see that's the only thing we did on Dexamethasone was this published in the BMJ.
We one of my students at the time who is now post-doc out of bed price,
wrote a paper with colleagues from all over the globe looking at what treatments were
being used routinely when people get admitted with COVID 19 during the first wave,
and you could see a lot of variation, as you can imagine, but you could see things like this.
You could see like in Asia, very, very little steroids, very, very little hydroxychloroquine.
Other countries like the US were using a lot of hydroxychloroquine here in the UK was halfway through.
So you could see this variation that usually demonstrates that you don't really know how to manage the condition, right?
And then these different clusters of, you know, countries that do things similarly, which is quite interesting as well.
And in there we saw for steroids in particular how, you know, very, very little use in Asia, more so in Europe and in the US.
Mm hmm. And and so should I jump to vaccines or was there another important study that
happened before we had the the opportunity to think about thinking about vaccines.
So I guess before we jump into vaccines, the other bit of that was very important was this work on prediction, right?
Oh, yes. Yeah. Because if you classify you again into these three categories.
Yeah, we found that it was relatively easy to predict somebody's risk of of having severe COVID.
And that was very important information because some governments with planning, you know,
shielding strategies or thinking how to roll out their vaccines when they were available.
In the end, it wasn't rocket science because it was relatively intuitive, I guess, but it wasn't quite like the flu.
Like if you try to see who is going to get very high risk of, you know,
ICU or hospital admission with the flu, you get like two pigs with young children and and elderly people.
With COVID, you had, you know, children were okay. Very elderly people also had problems.
But then you also had this group of people who were relatively healthy but had obesity, diabetes,
a very different metabolic profile that made them, you know, for some reason prone to having very severe complications from COVID 19.
And that was quite a finding than whatever people did with that information, different governments and different things.
Right. But I thought at the time that was very important information that we had to make available.
And again, that that I think informed some of the policies internationally.
And what was the mechanism quite interested in that kind of detail of how information flowed between researchers and the government.
Did you have a kind of hotline to the Department of Health? Yeah.
So, so I guess there were a number of ways things happened.
We were making all our data available in the form of Preprints in med archives mostly, and some governments and some even international stakeholders,
like the European Medicines Agency or the FDA, were very good at reviewing the literature every day and identifying studies that were relevant.
And we would get an email saying, Oh, we would like to know more about these.
Or sometimes the manuscript had enough information, then more nationally.
I also had, you know, been in touch with some of the colleagues in the Department of Health,
and I was very closely talking to them and telling them, look, there's this paper coming in Morocco tomorrow, see if it's of interest.
And if you need any clarifications, let me know. Yeah.
So there was basically this, you know, more proactive or more reactive attitude depending on what the information you were producing.
And I guess also the information that each country had already available because some countries were very data poor while the UK was very data rich.
So the Department of Health, I believe, had a lot of information coming from UK HCA as well as researchers from all over the country.
So I you know, we were very proactive in providing the information, but I'm sure they had much more data than many other countries did.
So it's about at what point do you think it became obvious that there was going to be a vaccine?
You know, it was looking good. We haven't actually got the results of the trials yet,
but the possibility that there would be a vaccine within a year of the pandemic beginning was looking looking good.
And did that influence your thinking about how to address that? Yes, very much so.
I think by the summer of 2020, which, you know, thinking about it is quite early on, amazingly fast.
Yeah, maybe. Maybe, of course, because I live in Oxford and then you, you know, if someone who is in a phase one trial,
you know, like I had a neighbour who was one of the first 50 or 100 people who were testing one of the vaccines.
Yeah. So, so we knew by summer 2020 that there were candidate vaccines that were, you know, going through a kind of trial process.
I don't think we knew exactly when we would have enough data to approve them, but but we knew, you know, this was moving very quickly.
So what that meant for us was that we needed to be prepared to help the regulators with their work on safety.
Yeah. And when it comes to vaccines, safety is paramount because, you know, if you're giving someone who is sick a treatment,
you're giving them that treatment to allow something to improve the quality of life.
With vaccines, we are basically trying to prevent something from happening.
And typically, not only people who are very high risk, but also potentially very healthy people.
Right. So so safety concerns are very important.
And so the way he works with with regulatory work is that once a product is approved based on the clinical trial data,
there are all these commitments for post-marketing surveillance.
And typically the first signals that the regulators get come from yellow cards and that's that sort of information.
They call it spontaneous reports of patients or physicians reporting that something has happened.
It doesn't need to be causal, but they just report something that wasn't in the label.
And it could be it could be a sprained ankle, it could be anything.
Yeah, they need to look at the narratives in those reports and then assess, you know, if it's let's use the sprained ankle example,
is this happening more than for people who are being vaccinated with flu vaccines, for instance?
Right. So they do a little bit of what they call a disproportionality metric.
Yeah. In any case, when they see something that they think could be potentially causal,
they then what they do is they they look at previous knowledge on how often that sort of thing, that event happened in the general population.
And how often are we seeing that in the vaccinated population. And they compare both, right?
And they do this type of analysis they call observed versus expected analysis, which I think is an interactive terminology in this case.
So of course, to have an observed effect is expected analysis.
You're going to need the observe. You also need the expected, which comes from historical data.
Right. And although you would think that we have information on the rates of any condition you can imagine, that is not true.
There are many things that are very important for vaccine surveillance that we did not
know quite how often they happened in the historical data in the general population.
So we thought the first thing we had to do was basically do this very accurate analysis,
stratifying, you know, into different groups of age and sex and so on.
On how often do you see these conditions that were potentially identified as potential safety signals to keep an eye
on before we had the trials so that the regulators had all that information by the time the vaccines were approved,
and this is people who had vaccinations for other things,
this would be either people who had been vaccinated for something else or in general in the whole population.
Oh, I see. So if you want to say, oh, I'm seeing more blood clots in this population that has been vaccinated than in the general population,
you need to know how often that happens in that general population,
and that is not always available maybe for blood clots it was, but for other things it wasn't,
because some of these things are very specific and not very common in general.
And we did a piece of work again with this community,
with the Odyssey community and colleagues across the globe looking at basically estimating all these rates
that we call them background rates or expected rates from historical data 2017 to 2019 before the pandemic.
And we had data from 16 or 17 countries that was published in the BMJ.
And I know from I've heard from regulators that they use that all the time because that was the first point of contact.
You know, when they were looking at blood clots, they would go and say, well, what is the expected number?
And they could do that calculation very quickly. And we did that for 15 or 16 conditions that they had.
I think the FDA had listed US adverse events of a special interest for surveillance of COVID vaccine safety.
So one of the other things I've heard people talk about.
What is the anxiety that you might get an exacerbation of the condition with the vaccine that it could make?
They could actually make the symptoms. Yes. I forgot what the proper term for that is.
Yeah. There is a term for that. And I know it's not quite getting to me now.
Yeah, I know. I know that is a concern.
I think that was relatively clear.
It was theoretically clear early on from the phase two trials that that was not happening for the vaccines that were coming up.
So that's always a concern. But the good thing with that particular problem is that you typically find out very early on the trial because, you know,
yeah, so having COVID, of course, is not a rare outcome compared to, you know, having a blood clot or something else.
So that was I think that was data that we didn't produce because it was already available in trials.
Yeah. So that was a the first kind of decision.
We had to produce that data as early as possible. And then the other decision was to start preparing, identifying candidates across the world,
but also across Europe, more specifically of people who we knew would have really good data on vaccine exposures.
Yeah, So, you know, I'm talking about people around the continent and also in the UK who had access to data with, you know,
vaccine brand vaccine batch, because there could be issues with specific batches, you know, specific date when a vaccine was given.
And that was we knew would be hard because we knew this vaccination campaign would be universal and
people would be going to the Kasama Stadium in Oxford or to become known in Barcelona to get vaccinated.
Right. So it's not like we would just go to the GP records and find out that we needed, you know,
data sources that had that ability to link or to identify people getting vaccinated.
And that was that is where it was very obvious that European data would be the best in the world for that because of the way we organise healthcare,
right? So a country like the UK or a country like Spain that have universal healthcare systems where you
can track a patient across the healthcare is much better because you have a unique number NHS,
because you have a unique number, and Scandinavia will be another example, right?
Compared to, for instance, you know, in the US where people basically have a health insurance,
but then that doesn't always necessarily link to a vaccination in a stadium or in some sort of centre.
So yeah, we prepared for that, knowing that at some point there will be a vaccine safety issue and we would need to produce later.
And I know if you want to discuss that in more detail, but that's, you know,
I guess the third bit of work that we did that was very impactful was investigating
some of the events as they as they were observed by some regulators and and those.
So you were once the vaccine rollout started, you were you you were monitoring continuously in these.
How does it work? Do you have software set up to to pick out any of these signals that something's going on?
So that's the work that the regulators do. All right. I see. They're the ones who typically will modify a signal.
And usually the happens before in the spontaneous report data that happens in the data I have access to.
But what we have is software that was capable of software and colleagues that
were capable of curating this data all the time so that when an issue happened,
we had access to recent data because otherwise, yeah, you basically don't have enough information to do the research.
And of course the the data that the regulators have, these spontaneous reports are very limited in that,
you know, they are low in numbers, they don't have enough information.
They don't have either nominate or you don't know how many people look like that person that reported that problem.
There are issues with completeness. Not everybody reports when they have an issue,
but they are very useful as a kind of signal detection system where you can pick up something that's surprising.
Right. And then we were basically ready to go.
I mean, there was something that was indeed surprising to, you know, a more elaborate kind of evaluation of that specific signal.
Mm hmm. And how did that play out?
Um, but obviously, there was I think everybody remembers that there was this sudden concern about the possibility of blood clots.
Yeah, the numbers were tiny. Yeah.
So I think in relation to the AstraZeneca vaccine, so the blood clot one is one that I think we contributed a lot of data to.
So there was, yeah, basically, I guess mostly the UK national regulator and the European Medicines Agency were the first
ones to see this signal because these vaccines were not heavily used in the US initially.
And then they basically the minute they said there was an issue with that, we had the background rates that I mentioned before.
We could we could see whether there was a very clear increase already and we didn't see something very, I'd say, spectacular.
It wasn't something that I mean,
they were talking about something very clear from the spontaneous report data that we were not seeing something that clear from our data,
which was reassuring in a way. But then, of course, we needed to then say, okay, let's do a cohort study where we followed people up,
you know, and observed how many of them had one of those blood clots in their first 28 days after a vaccine.
And yeah, so we did that in collaboration with partners across Europe again, and we were the first to produce that international bit of work on that.
That was the first bit of more, let's say, you know, rapid evaluation and using these, you know, expect to observe the expected type of analysis.
And then after that, we also said, look, if if this signal is going to be observed for people vaccinated with these specific vaccines,
why not compare them to the people vaccinated with the other vaccines to see whether,
you know, they will be more comparable than comparing them to, you know, people from 2019.
Right.
So that was the second bit of work that we also completed using data from, I think, six European countries and US, and that was published in the BMJ.
And and very, very welcome. We did observe little signal for thrombocytopenia, these reduction in blood clots, in reduction in platelet counts.
And then a little bit of a potential signal for blood clots, which kind of, I think, you know,
reassured us that the data we had produced before was was in line with that as well.
So that was for the blood clots. And the other issue that I don't think is entirely resolved yet is this problem with Guillain-Barre syndrome.
I don't know if you've heard right. Yes, I have. That's a neurological inflammatory condition.
And there were some signals coming up again from spontaneous reports on Guillain-Barre, but also on Encephalomyelitis,
another inflammatory condition of a different part of the brain and also Bell's palsy or facial paralysis.
So we did an analysis of those three in data from the UK and Spain, which were the later we had more access to one and you know,
that were of better quality and found in our analysis, which I think were quite, quite accurate.
We didn't find a signal for any of those three. But interestingly, we found that when people have.
The risk of having those conditions is increased by like three fold.
All right. Which I think was reassuring because at the time, again, the counterfactual of not getting vaccinated was getting it right.
Yes. I was going to ask you about that in relation to the blood clots, because, yes, I looked at that.
We will look at that and we saw a similar thing. I think we knew that already.
I think so that the risk from getting COVID of these adverse events is much higher than the risk.
Much, much higher. Yes, I think maybe I didn't point that out earlier because I think we kind of knew that all of us who are
clinicians knew that because one of the reasons people were dying when they had COVID was blood clots.
Right? So we were very worried that, you know,
people were scared of having a blood clot in half a million people when actually when people got COVID, it was like one in a thousand maybe.
Right. So that was but, you know, on paper, that was very, very clear.
There's a yeah, five, ten fold increased risk of things like, you know, pulmonary embolism,
some blood clots in your lungs with COVID compared to a potential increase, which wasn't even significant in this case when you had the vaccine.
So the kind of. Yeah. Risk benefit again. Right.
So the the the problem when when you had the infection was much, much worse than when you had the vaccine.
But I guess the in the public mind, having a vaccine is something you choose to do to yourself or have somebody do to you.
Yeah. And in a way, you feel you've got control over that.
You can take a decision whether or not to get it and with it, whereas catching an illness is just bad luck, I suppose.
I don't know. I'm trying to account. Yeah. So the way people seem to be more fearful of possible risks from vaccines than they are the disease.
So I guess my argument against that would be actually in a way, you are choosing whether you have the vaccine and the vaccine protects your arms.
ABC is right. So it's not only bad luck, it's also if you choose not to have the vaccine,
then you are much, you know, at a much higher risk of having a severe form of the disease,
which is what leads to these complications, because, of course,
we also did a study looking at what happens if you have COVID in the ambulatory setting, like, you know, in a home.
Right. Or in hospital.
And the people who are in hospital that had a much, much, much higher risk of having blood clots when they had this severe form of COVID 19.
So in a way, you know, yeah, I do appreciate what you mean.
Like when you obviously put in your arm there to get a vaccine whilst people probably had this idea that, well, COVID is just bad luck and you get it.
But basically there was this intervention that was preventing you from getting it, or at least clearly preventing you from having a severe.
I'm not saying it's rational. No, no, no. I know. I know how to work with the kind of rationality about it.
But it's it's just this, you know. Yeah.
I guess as scientists and especially in epidemiology, we always work with counterfactuals, but we don't like to give you one number.
We like to say this is the number if you do this, but this is the counterfactual if you don't do it.
So, you know, to us it was important to produce this knowledge on what happens when people have COVID without being vaccinated,
you know, And that was that was our our thinking, both with the blood clot signal and with the neuro inflammatory signals.
And again, with those, to my surprise, because I didn't know what to expect, really, we we did see, again,
a very high risk of having these newer inflammatory complications when people had COVID and were not vaccinated.
So, again, that was very reassuring data to say if you are scared of blood clots or if you are scared of having Guillain-Barre,
what you should do is actually get vaccinated. Yes, yes, yes.
And and that, I think, was important not only to reassure the regulators and, you know, to inform future research,
but also hopefully to inform the population of the importance of of vaccines getting getting vaccinated.
And have you looked at long COVID at all? So that's an ongoing project we're doing right now.
We are looking at whether and this is and again, NIH, National Institute for Health Research Grants that we got about,
I want to say nine months ago to look at whether being vaccinated prevents long COVID.
And this is something someone could have looked at in the vaccine trials, but long COVID wasn't a concern when we did those trials.
I mean, you know, it's going to be very hard to think that somebody wouldn't do a trial of vaccination versus not vaccination of age.
Right. So we are doing this with the kind of data we have information on.
We are finalising those analysis right now. So I'm hoping we will have results by the end of this month, but it's looking quite promising.
I think we will have very, very good, very compelling evidence that vaccination is also a good idea to prevent long-covid,
which is what we kind of expected based on anecdotal evidence.
But there is. There's a systematic review of the literature by UK agency showing that there is a need for this specific type of study,
and that's why we we are doing it. So there's no question now.
I mean, I think early on when Long-covid was being talked about, I think even the term long COVID was developed by patient groups because there
was a lot of scepticism in the medical community about whether it was real. And is that something your studies have addressed?
So this is something we have looked at already, what we've done.
I don't think we can with the data I have, I don't think we can look at whether long-covid is a thing.
You know, I don't think that is something we can do.
I tend to believe that if patients explain an experience they are probably having, and so I never hesitated of that.
But what's really important, I believe, and what we need and is research the all this research on long COVID,
we've been working with long COVID patients very closely.
So it's been very much informed by patients themselves.
But one of the things was, you know, we have a list of 25 symptoms that the W.H.O. identified us,
you know, to be used as a definition of long COVID clinically.
So this is what clinicians do nowadays, is they see whether people had those symptoms for more than three months.
And if you have one or more of those for more than three months, then you officially have long-covid.
And that type of new is it called post-COVID syndrome.
Now post COVID? Yeah, I think they could pass quite post-acute COVID syndrome as well.
As long COVID remains the the the I guess, yeah,
less formal terminology and the most official one is that it's passed, but it has this definition by the W.H.O.,
which comes from an expert group and, you know, who sat together and said, this is what my patients have and that's what we are using.
But I think that that can be refined and the kind of data we have access to can be very useful to really find that.
So before looking at, you know, do vaccines prevent long COVID,
we did a lot of work to look at what that long COVID actually look like in the data and what we did,
which is quite interesting and has not been done before.
And this is something that will hopefully be out in the literature very soon because we've submitted the paper and everything is looking at, okay,
what happens if I get a person who had who tested positive for COVID and I compare them to a similar person with the same age,
gender and so on, who tested on the same week but tested negative.
Yeah, there are some of the symptoms that are listed in the W.H.O. list,
like chai tea that I think all of us were probably experiencing to some degree when we were in the middle of lockdown.
Right? So we really wanted to see whether there was which of those 25 symptoms had really difference in the
duration or the severity or their presentation in people tested positive versus tested negative,
who looked alike.
And we've done that work and we've I think we're going to provide very important information on what are the symptoms that are more differential.
I'm not saying that patients with long COVID didn't have on chai tea. What I'm saying is if we know which of those symptoms are more specific,
maybe it's the words to Long-covid that could help us do research on those specific mechanisms.
Right? So imagine if we just said, well, people with long COVID have ten times more risk of having cardiac symptoms like palpitations,
chest pain and something else than people who tested negative.
Clearly, there's at least a group of people who have a heart condition that should be investigated.
Right? What if we say in chai it's not differential, for instance, then maybe that is not something we should be investigating so much.
We should treat it, of course, because we should treat everyone with that condition.
But I don't think that is then something we should think is involved in the issue of pathogenesis,
as we say in the causal, in the mechanistic, uh, processes that happen before people have have long COVID.
So that's what we've done and we're going to publish very soon. And it's very exciting to see how this kind of analysis can, you know,
and rather than new knowledge and new mechanisms to understand more about this
condition that's intriguing and affecting loads and loads of people in that analysis,
we also looked at whether there was a way, a wave of long-covid every time we had a wave of COVID and whether that changed over time.
And we did see that that was true for the first few waves.
But it looks like at the end, like from Delta onwards, probably because people were already mostly vaccinated,
we do see less of a wave of long-covid after each wave of COVID in the community.
So that again, is, I think, very important planning for what right.
And how many people come we expect will get COVID after having COVID?
And do you still have questions to ask about COVID? I mean, we're I think we're being encouraged to think, oh, it's all finished now.
But, you know, you look at the data and I mean, there are still quite a lot of people around.
You have it. Yeah. So we are doing a fair bit of work on maybe smaller things now.
Maybe. On such big data in terms of numbers of people, but rich of data in terms of numbers of variables in a given dataset,
we're using a lot of UK Biobank data, for instance, now looking at genetic traits associated.
We, for instance, published a paper showing that there are some,
some genetic traits that predict who is going to have a blood clot after having COVID, for instance,
which is very important because you could potentially consider doing prophylaxis prevention
of sorts in people who have genetic markers of high risk when they get COVID right.
So we're doing work on that. We're doing work on genetic markers of breakthrough infection, genetic markers of long COVID.
So all all of that is work ongoing in the team right now as we speak.
And in the meantime, if you you've you're still doing your predictive work or going back to your predictive work on cancer.
In the meantime, the team is also looking at controls in cancer,
predicting cancer and looking at the use of machine learning and artificial
intelligence to classify cancer being better so that we can treat it more accurately.
I guess is the is the way to say it. I mean, of course, the team has grown quite a bit.
My team has grown quite a bit since the pandemic because, you know, the amount of work that we're doing is,
I think, probably three fold what we were doing as a consequence of the pandemic.
I would probably say so because of course all this work on COVID didn't exist, right?
So we have to do that that we were not doing before. And there was this deep prioritisation exercise that we lead for a while where we said, Well,
the most important thing now is to figure this out, but now we have to go back to also answering other questions that matter.
Like, you know, this issue I was talking about in elderly people who are taking these medicines, Right?
So we are now, I think, trying to answer all those things in parallel.
And that requires more resources. And and we do have that.
But do you think the value of your own group and the net, the wider global network has been recognised?
Has your profile been raised? Absolutely. Which will help with getting more funding for people?
Yeah. Yeah, absolutely. So we we have so in I was going to say in the middle of the pandemic, by the end of 2021,
we had a very large European grant to look at this issue with cancer that I was mentioning.
And more recently just a year ago, we we got a very large contract from Erasmus Medical Centre and the European Medicines Agency to do this work on,
you know, looking at the safety of medicines and so on internationally.
So so at the international level, 100%, very much increase at the national level, I would say so as well.
And I mean obviously a work question perhaps doesn't apply to you because your work has always been very collaborative.
It's nationally and internationally.
But did you have a sense that working during the pandemic was that people were more prepared to collaborate and you wanted to work together?
And so that the normal kind of cut and thrust of academic competition was less less of an issue?
Yes, definitely. I think I think specifically for I mean, to be honest, at the beginning, COVID was not bringing any funding to anyone.
We were just doing it because we had to do it right.
So when I was talking about, you know, growing the size of the team at the beginning, it was basically the same people working more hours.
So it wasn't a funding competition as such. It was more, you know, I guess, competition to produce useful knowledge.
Yes. And I think, yeah, I want to be optimistic.
I think I think the pandemic in a way catalysed a move towards more collaborative work, at least in my field, in heavily the sciences.
I would say probably, Yeah, I think so. Okay.
I'm going to come along to to talk a little bit about how it impacted on you personally and how how you work.
So, I mean, first of all, how threatened did you feel by the virus itself yourself personally?
Yeah. So let's say probably because I had access to a lot of information, I was, I think,
more scared than most of the population much earlier than most of the population.
Yeah. So, you know, I think this is a very nasty virus that before vaccination is still nowadays very risky and very dangerous.
So, you know, not specifically because I have any particular condition or anything,
but I knew it was a was a virus that was causing, you know, even in people like me, healthy and relatively young.
A hospital admission in every 100 which is you know, if you are if you do the math it's a lot of people in hospital.
Right. I, I am also someone who travels a lot for work, who interacts with a lot of people because of collaboration,
who meets people in a room like this all the time.
So at the beginning when when we were, you know, starting to say, okay, it's clearly here because it's until the end,
it's in Spain, and we're getting like, you know, hundreds of people moving in in both directions every day.
It to me was very scary because I was kind of very confident that I had all the chances to get it.
And because there was this, you know, uncertainty on how long the incubation period was,
I was also scared to pass it on to my partner and to my children, right?
Yeah. So it was it was very scary at the beginning. And I think it was still scary for a very long time for me until we were vaccinated.
And at that time I knew it seemed quite different and we were moving into a completely new stage of the pandemic.
And Did your team work at home? Mostly because, I mean, most of your work is with computers.
Yeah. Most of the work you don't. There's no work.
There's no patients. Exactly. So, yeah, so the only value, which is a lot,
but the only value of being here in the partner Research Centre where we work is that we meet all day long, we go to each other to ask questions.
There's much more opportunity for solving problems together and and for brainstorming and things like that.
But the work can be done mostly online from home, really.
So yeah, I mean, the way that we knew this was coming and there was going to be a lockdown, I basically told everyone, Feel free to work from home.
And, you know, I knew I knew that that was coming.
And me what's going to happen, you know, earlier or later. So so we all worked from home.
The team was impressive in their, you know, in how they worked and delivered everything.
Despite the massive change and adaptation, I have a lot of colleagues who are, you know, from other parts of the world.
Some of them went back home or, you know, or what their families wear, and that still worked out really well.
So yeah, I think it demonstrated the resilience of, you know, a team of people that really wanted to make a difference, despite all the odds.
For me, uh, maybe it made personal, but for me particularly was also a way to kind of keep busy, you know,
sometimes of feeling useful and, and probably as a physician myself, you know, feeling that you're doing something to help.
Did you consider going back into clinical practice?
I considered that every single day, and I hadn't been involved in the management of an acute patient for a very long time,
so I knew I wasn't the best person to do that, really.
And I knew that there weren't that many people in the world who could do the research we weren't doing.
So I you know, but I still every day I woke up in the morning thinking, should I just, you know, go and help in the hospital.
Right. And there was a point in January 21 or December 20, maybe when I was very close to saying, yeah, this is the right thing to do now.
But yeah, I mean, I managed to help clinically in other ways.
So I was helping with the rheumatology here and all the junior doctors of younger people who probably are, you know,
more up to date with the management of acute patients despite being rheumatologists were deployed in the cold wars and we were
basically covering mix so that you know in a way I was doing my bit clinically and did you have to get into full PPE and everything?
Was it was it was it it was mostly this hospital COVID free zone?
Yeah, it was this hospital, the National Orthopaedic Centre is, you know, it was relatively safe space or all the time,
but also a lot of the rheumatology work could be done online because sometimes, you know,
it's a consultation that's more about, you know, you have inflammation in your joints and so on.
I'm not saying it's the same as seeing a patient face to face, but, you know, again,
considering the risks and the benefits of seeing someone relatively, you know, with on treatment with immune suppressants and the kind of treatment.
Use in the clinic wasn't desirable.
Also, you know, most patients didn't want it either at the time.
So, yeah, you know, I had that every day. But but in a way, the amount of research I was doing was also so, you know, so, so big that I was busy.
I was working every single weekend. Yeah. I thought that was the other thing I was going to ask about how your hours changed.
I mean, I'm sure you work long hours anyway, but yeah, I mean,
it's it's hard to say how many hours we work because we don't have a kind of office, especially for us or, you know, mostly MIA.
But at that time it was crazy and unsustainable.
Clearly, it was just something temporary that we thought, you know,
I guess we we kind of kept going because we thought it would be another two weeks and then it would be another two months.
But I guess recognition should go to our families and the people who supported us during that period,
because in my case, it was yeah, it was very, very crazy.
I still remember the first time I was watching a movie on the weekend with my kids and feeling guilty that I wasn't working,
you know, And I was like, well into 2021 already or the previous year.
And it was basically just work as much as you can because this needs doing.
Before yesterday, everything COVID was urgent, right?
There wasn't anything that you could, you know, basically try and and, and take more time to produce.
So yeah, that was clearly unsustainable and desirable.
But the only thing we could do at the time and you said you hinted that the the
fact that you had an important project to work on did support your wellbeing.
Yes. So for me it was important. And I and I think if you if you interviewed my partner, she would say the same.
It was my I guess it was one of my May I also exercise talent.
I didn't did Yeah. We were able to but it was clearly a mechanism for me to Yeah.
To basically, you know think more of the others than of myself you know, and, and create this knowledge that was heavily needed.
And rather than worrying about, you know, what happened if I get the virus.
Um, also it's true that of course working from home as I could do for all the work that we were doing, felt very safe, really.
Uh, although sometimes boring and, you know, and not very interesting.
Yeah, I think we more or less got to the end with COVID. Just about covered everything there.
Um, so yes, final question. Has the experience of working on COVID related research topics changed your thinking about how you work and what you do?
And is there anything you'd like to see change in the future? It has.
It has a lot. It has changed the way we do things in my team quite fundamentally, actually.
So in the past we were more reactive and I think we are now much more proactive.
Like we want to make sure that instead of having a question and then writing analytical code to crunch the numbers,
we now are producing software that will be ready to go to produce that data that we will need.
Basically with, you know, a line of code and a click rather, and, you know, three days of work coding and then quality checking and all that.
So we've moved into a space that probably is closer to, I guess, software engineering where we try to have pipelines, as we call them,
to be able to produce those data or that information very quickly in a very reliable manner,
rather than being reactive and saying, Oh, now we need to do this, let's see how we do it.
So that's we've been able to find commonalities between different kinds of questions and yes,
streamline your your software and the standardisation of data.
The mapping of data that we discussed earlier facilitates that a lot because, you know,
if you if you know that the data is always going to look like this, you can always write code towards that format, right?
And then tested in different datasets and so on.
So it has changed fundamentally the way we do, you know, have data sciences, as we call them, to basically be faster and more scalable, if you like.
Scalability is probably the word that we use in this community.
Mm hmm. Terrific. Thank you very much.