I'm Richard. I'm one of the team running the course this week where money one of the modules on this program,
which is a central medical statistics, about half the audience of students from that module.
Whenever we run a module, we try to have a seminar speaker who is relevant but diverting and off syllabus, something that's fun, Balaban examined.
And to be honest, when you want to talk about statistics, you have to try really hard not to invite Martin Landau.
Last time we spoke, it was about the life expectancy of left handed cricketers.
And we're pleased to have Martin back.
And just this morning, our students were studying plant opening plots or planned plots, depending where your loyalties lie.
But either way, it's one of the most highly cited papers as the most highly cited paper in The Lancet ever.
Yeah. Yeah. You're probably sick of hearing people mentioned that it's one of the 30 most
highly cited papers ever of any kind on anything anywhere in the universe.
Now, you got that right.
Not not as highly cited as David Cox. Yeah.
Okay. Well, thank you for coming. But if you make it stop. Okay.
Thank you very much. All right. Well, I'm going to talk today about diabetes, blood sugar and red wine.
This is a personal study and you'll see why it's a personal study.
All the data we're not only collected by me, but provided by me as well.
It was published in significance the the magazine of the Royal Statistical Society, which I recommend highly.
It's very interesting and very publication.
And I found it to be that a place where I can publish things that no respectable journal is going to take but are often,
you know, much more illuminating than what I get into the Lancet.
So I'm an emeritus professor, so that means they're not paying me any more.
I just do it for fun. So we'll see if we can have some.
Okay. Now, this is all about me.
I have diabetes, I have type two diabetes, and I was diagnosed around the beginning of 2001.
It was a shock because I expect to be told that that was what it was, but not a great surprise because I am the descendant of many type two diabetics.
Both my mother and father had Type two diabetes. Both my grandmothers had Type two diabetes.
My grandfathers, we don't know one died as a young man in an accident and the other died in the trenches in the First World War.
So we don't know about them. Several other members of my family have had type two diabetes or currently have it over.
My two sisters, one has Type two diabetes, the other doesn't.
She has hypothyroidism, which an endocrinologist assured me is just a different expression of the same genes.
So, you know, we're full of it. And one of the things I had to I was asked to do a course of my new status as a diabetic was to make my watch,
to measure my blood glucose every morning, fasting blood glucose, that is before I've had breakfast.
And you do this with a little finger prick to raise a drop of blood.
And that is a picture. I do all my own stunts, that's my blood and that's my metre and that was my glucose, but not fasting.
Of course I did this specially for the presentation and the and so a number appears that and it's supposed to be below.
Well, currently, I'll tell you, I'll come to it now. I love data.
So I began to I began to enter this into a computer and I began to analyse them and watch the graph falling as the blood glucose fell.
Because I was taking the medication and I was watching my diet and not taking things which I was told would deadly, which really surprised me.
The most deadly thing I had in my diet was orange juice.
I thought it was supposed to be good for me, but apparently it's terrible because it's full of sugar and my blood glucose came under control.
The initial measurement by my GP was 24 millimetres per litre and my first fasting blood glucose that I made
measured before breakfast was 19 milli miles per litre and the target was less than 7 million gallons per litre.
So I was quite a long way to go, but I made it and I eventually reached that mark.
Seven. And then for several years my fasting blood glucose remained comfortably below this limit and I stopped worrying about it.
I was so use by then too, this diet without sugar and so on.
And yeah, you know, everything was going very smoothly.
Nothing interesting was happening and I stopped recording it. Oh, what do I do then?
Hit the wrong key. Right. There's a second measurement used to monitor diabetes.
HPI 1c0 glycosylated haemoglobin.
And this requires a much larger sample of blood.
They stick a needle in your vein, suck it out and send it to a lab and you get the result a few days later.
And so that's always done as a clinic.
You can't do it at home and it measures the glucose exposure over the past few weeks rather than over the past few hours,
which is what the blue blood glucose measurement does.
And it's the measurement that doctors prefer to use to monitor diabetes.
Now the method of measuring blood glucose changed.
It changed from the concentration of glucose in the blood to the concentration in serum that is in the liquid component of the blood.
And glucose is highly soluble, as I'm sure you all know, and it is nearly all in the liquid.
So when they changed the ace, it went up.
I didn't notice that it had been changed. I noticed that the colour of the plastic strips I put into my little metre had changed,
but my glucose went up and I thought, that's funny, I haven't changed my diet or anything.
I was still taking all the drugs. Why has it gone up?
And then my wife said, You haven't looked at the leaflet in your in this little box because if you do, you'll see that it's changed.
And so I realised, yes, of course it's gone up because the way of measuring it has gone up,
not because the actual thing has gone up and the upper limit was now around eight months.
Sorry. Yeah. So eight miles per litre and the units of measurement to HPI well see also changed from a percentage to barely moles per litre.
I went to see my GP and she said to me, your HPI one C is 75 and I said, I guess 75.
She said, What did you think it was going to be? I said, 6.5%.
She said, Oh yes, we've changed it to millimetres per litre. So many miles per litre it became.
And so that was that was all right.
But it was still a shock because 75 millimetres per litre was a very high value, she said.
It should be 59 or less. So I was out of control again and I knew it had gone higher.
But you know what, with the change of units and so I haven't really appreciated it very much.
And so I thought, right, you've got to do something about this.
If you don't, they'll put you on insulin, you'll have to inject yourself.
And I didn't fancy that. I thought, I'll leave that to I'm older. So I decided to go for a more rigorous diet instead.
Not only would avoid sugar, I would cut out most of the carbohydrate.
So usually now one piece of bread in the morning is okay.
That's it. That's all I have. Just to show you what a health freak I am.
I bake my own bread without any salt because I also have very high blood pressure, although the drugs keep that down to something really good.
So I thought I'll also. Yeah, no more potatoes.
I'll try harder to avoid beer and wine. I won't cut them out altogether.
That is asking too much, but they are vehicles for carbohydrate and sugar.
And so when I drink alcohol, I'll drink red wine.
And I also resume recording of the daily fasting glucose to monitor the effects.
Oh, I've done it again there. And this is what it looks like over several years, day since the 1st of January 2012.
And you can see that at first it goes down in a very good and encouraging way and you can see that's going down over that first year,
down below that new limits of eight. And then the next year it went up again, hovering around it and then below and it chops and changes.
It goes up and down and occasionally that shoots the go shoots up like that.
I know what that was. That was at the International Biometrics Conference in Florence.
Believe it or not, we went to a 2 to 1 of the restaurants that a tasting restaurant, and it was tasting enormous amounts of pasta.
It was a nightmare. Oh, okay.
So it rises and falls, occasional spikes.
The medication was increased. Was Del changed at several points.
And as you can see, the HCA one see rises and falls with the fasting glucose, as you might expect.
Yeah. So I thought, oh it might be interesting to see whether I can predict the HPI one C from the fasting glucose.
You know, I don't know what my HPI one C is, but maybe I can predict it.
I am a statistician after all. So I thought, well the pre, you know, they said the preceding few weeks, how about six weeks.
I said right 42 days and it worked.
Then I tried a longer period, tried 60 days and it worked better.
So that's what I use now. And there is a predictive.
Shin of my blood glucose to predict my HPI one C and you can see that quite a lot of measurements in
there and that's the regression line and the confidence interval for the prediction and the one in read
the 59 that is the value of HPI one C predicted for the 16th of August 2017 when I had blood taken and I
had to arrange it because I was going off on some conference visit and I thought it's going to go up,
so I'll get it measured before that happens. And, and the measured value is 59.
So I thought that was fantastic, you know, prediction and measurement coinciding.
Exactly. My wife, who features again in this story, Shira,
one day that she noticed that my blood glucose seemed to be a bit lower on days after I'd been drinking.
And so I thought, yes, you might be right there.
So I thought, well, I will add a record of my wine drinking to my daily glucose record and a prospective data
collection to test the hypothesis that red wine was associated with reduced blood glucose.
And I thought if this works out well, that be fantastic.
You know, I can have a drink and think I'm doing myself good.
I also recorded an other alcohol variable, which might be white wine, beer,
whisky, whatever, because I thought that these might increase blood glucose.
Uh, yeah. Sherry gets counted as other alcohol because it's white wine.
The pork gets counted as red wine because that's what it is.
And so I thought all that alcohol might increase blood glucose because white wine and beer are vehicles for sugar and carbohydrate.
So I planned statistical analysis with I would do a two sample tea method for red wine days versus
no red wine days and a multiple regression of glucose on red wine and other alcohol jointly.
And the hypotheses for that were that the effect of red wine and other alcohol would be opposite,
and also the alcohol consumption would not be independent of red wine because on social occasions I might well drink both.
So I decided to write an article about this in 2017, March the 27th.
It was I know this because it was at the meeting to celebrate the 20th anniversary of the Centre for Statistics in Medicine.
And at the dinner, I was sitting next to the editor of the BMJ and we were chatting.
I told her about this and we agreed that it might make an interesting article for the Christmas BMJ.
And I was very happy about that.
And on the morning after this dinner, I had a very high fasting blood glucose of 6 to 9.0 millimetres per litre.
And that was because I'd been drinking red wine and sparkling white wine and lots of food.
And now I'd been monitoring the comparison between my red wine days and other days, you know, just doing the occasional t test.
And this day increased the running value for my significance test.
And I thought, Right, well, we know that repeated significance testing is wrong, but I'd only be doing it for my own interests, so that didn't matter.
But if I was going to publish this, I would need to set a date for a formal closing of the data set and not look at them again.
So that's what I did. And I didn't want to invalidate the whole thing by choosing the final date just because the results fit the theory.
I know that there are people who do this, but I hope none of them are statisticians.
So I chose to use June the 30th because that would allow time to prepare an article for the September deadline for the Christmas BMJ.
This is how real science works. And so that now you go.
That's June the 30th, 2017, going from the 12th of December when I first started doing this.
So, you know, it's nearly 200 days.
And as you can see, the difference is small but apparent.
It is statistically significant. The confidence interval is -5.51, 2.06 many miles per litre.
And I thought that that was good evidence for a relationship between red wine and glucose.
Normal distribution with uniform variance followed quite closely, apart from a couple of outliers of one rather dramatic outlier.
That was the. Obviously another wild night wasn't the one in Florence, but a different one.
And and curiously, on a day when there was no wine, I don't know how that came about.
And the sample is quite large, you know, nearly 200 people.
Equal sized groups. And I know you want to know.
And I drank red wine on slightly more than 50% of the day.
And that so that seemed perfectly valid, except that the assumption of independence then, of course,
the analysis ignores the fact that the glucose measurements from day to day are related.
A high glucose day tends to be followed by another high glucose day.
You saw the way that thing goes up and down. Stuff.
But so the analysis is only approximate ignores the auto correlation and there are the sequential P values.
I thought that would be interesting. As you can see, when I started to do it,
the P value was not significant because there were only a few observations and it fell and fell very satisfactorily.
That's why I decided to write the article and then it went up again and for a few days it was above the red line and then it went down again.
And if there were a genuine difference, we would expect the p value to tend to get progressively smaller as data were added, which it does.
So I think that that's fine. If there were no true difference, we might expect the p value to go up and down in a random way,
except bearing in mind that each p value is linked to the one before, so they would sort of zigzag rather than be just scattered.
The test was statistically significant when I decided to write the article on day 87, but around day 140 it ceased to be so.
But it became significant again before my predetermined analysis.
That's very important. My pre-determined analysis pie and the trend was down with.
I illustrates quite well how dangerous repeated significance testing is.
Don't do it a thing, you know.
If you keep doing it and then pick one of them out, it can be highly misleading.
We should decide what we're going to do and when.
Before we start now, I didn't in this case, but I decided well before I decided when I was going to write the paper.
We must not keep adding data and testing it until we get the results we want.
But the overall evidence to support the red wine hypothesis, the other alcohol that was associated with red wine,
is that it will be being consumed now 14.1% of red wine days and 5.4% of days without red wine and the multiple
regression estimate so that the estimate for red wine is -0.31 miles per litre on days following wine.
And that was highly significant piece point nought, nought.
And I'm very close to the point, not one that I had for the T test and the confidence interval is also very similar.
So very similar results, the just slightly more significant, slightly narrower interval.
And the estimate for the other alcohol was plus .26.
So it went up, but it wasn't significant. The confidence interval goes from minus point 1 to 2 plus 0.64.
Hence the other alcohol was associated with an increase in blood glucose, though not significant.
And there are the serial P's for that. As you can see, it's quite weird.
For the red wine it goes, it bubbles about falls and stays down below the limit all the time.
For the other alcohol it goes down is much more dramatic, but then it goes up again.
So why that should be? I have absolutely no idea.
And it had an effect very early on, but that significance disappears towards the end of the period, saying it may be spurious.
However, again, it illustrates how misleading these significance tests are.
Repeated significance tests are well supports in my theory that other alcohol would increase blood glucose, but it just didn't prove it.
The evidence crumbled as I continued, and it's not refuted by the non-significant fact.
The data are consistent with an increase of 2.64 millimetres per litre with no difference and consistent with a decrease of .12 millimetres per litre.
More data in the future may cast further light on this. Now there are a few caveats here.
This is an observational study, not an experiment.
We must be very cautious about inferring cause and effect.
Drinking red wine is not random, okay.
Tends to happen. Weekends tends to happen when eating out, for example.
So my wife and I had a night out on Tuesday and we shared a bottle of red wine.
And how can I put this? We didn't waste any of it.
I'd have guessed that eating out would, if anything, increase glucose.
But this is pure, pure speculation. It did. That particular one certainly did.
We've also noticed that my glucose appears to be higher after I've eaten.
Correct. Why that should be? I have no idea, even though I usually do this without rice or other carbohydrates.
But because curry contains a number of pharmacologically active substances such as turmeric and who knows what they do?
Well, I'm sure many people do know what they do. I don't know what they do.
And Curry implies no alcohol consumption. If I'm out. How often?
A beer if I'm out. Now the details of food are not recorded.
All I can be said is this rather weak evidence of an association between blood glucose and red wine consumption on the previous day,
even one person with diabetes. So I'll have a look at the literature.
If you're going to send this paper off. You know, having done all this, you better say you find out has anybody else done it?
So I did a search and I looked at red wine of fasting blood glucose.
And here is a systematic review by the Oxford team, I should say.
Geoff Aronson commented on this article for me very kindly.
And they reported a systematic review of randomised trials of the effect of alcohol intake upon glucose.
They reported no overall evidence of an effect of alcohol on blue blood glucose,
but did not distinguish between red wine and other sources of alcohol.
Gatineau as well managed to randomise 224 people with diabetes who usually abstain from alcohol to a daily drink of red wine,
white wine or mineral water. You know, I mean, how do you get people to agree to this?
Yeah, it's amazing. Managed to retain 87% of them for two years.
Whether they stuck to this for two years, I don't know. But they allowed the measurements to be used.
They reported significantly lower fasting plasma glucose with white wine compared with water and a small and non-significant reduction with red wine.
But there do appear to be problems with the design of this study.
As Dirk pointed out to me, he published on this.
Why don't I read all these articles he was implying? But it was a letter.
And he said the actual allocation was pretty ropey. And when I looked at it in detail, I agreed with him.
So that's a dodgy study. Shares how randomised 109 people with type two diabetes to red wine or alcohol free diet beer for three months.
Why? I don't know. But they got a significant reduction in fasting blood glucose for the red wine
group compared to the beer group codeine as how they had a crossover trial.
And I randomised 20 women to drink 190 miles of red wine.
That's a large loss on five days per week for ten weeks and abstain from alcohol for ten weeks, you know.
Yeah. Oh I just give people drugs. They reported that mean a nice day.
Fasting glucose was 91.1 and 9.2 milligrams per decilitre at baseline 91.6
following red wine and 88.5 following abstention with no significant differences.
So they certainly didn't agree with me, but they disagree.
And an uncontrolled study of 42 subjects setting out.
After all, this is the hardest paper to get hold of reported that after daily consumption of 25 miles of red wine for two weeks,
blood glucose increased slightly. And this one I like Ginette.
How nominative determinism in action.
Jen has reported the amount which glucose rose after a meal taken with red wine was less than when compared to water.
A similar result was found for tannin taken after the meal, but no difference for alcohol.
Which was very interesting because it suggests they might be the tannin rather than the alcohol in the red wine, which may have an effect.
So it's not the wine this, but the redness. So that's an interesting idea.
But they didn't report fasting blue glucose, so we don't know about that.
I could find no report of the effect of a single dose of red wine on fasting glucose.
I came across this paper by holds that are reporting that regular alcohol consumption decrease the risk of developing type
two diabetes and the lowest risk it was estimated to occur at 14 drinks per week for men and nine drinks per week for women.
They didn't distinguish red wine consumption.
While it's very nice that their optimum figures coincide so well with the Department for Health recommendations for what you should be drinking.
So, yeah, so when people tell you one drink is enough to kill you, save would be might stop me dying of diabetes.
So that would be a good thing. You know, every I know that we I will die.
You know that will happen. Yeah. So what next?
I thought. Would it be feasible to do it? Oh, yeah, but before I thought about what next.
Oh, right. Okay, so you've reviewed the. You've done the analysis, you've collected the data, it's SEP, send it to the BMJ.
So I sent it to the BMJ and they turned it down.
It's not scientific enough. They said I was not scientific about it, but they didn't tell me that.
It just said it wasn't scientific enough. So I thought, Well, I'm not going to worry.
I met the editor of the BMJ later at a very sad occasion and she she said, Well, how about that red wine paper?
I said, Oh, I sent it to significance and they published it. She said, Oh, yeah, I thought you'd have something like that up your sleeve.
So it's all right. So everybody's happy. We're all friends.
So what could we do? How could we do a study? Could we do a trial?
I thought, well, in principle, I could randomise myself to drink on some days, but not others.
But I think this will be unlikely to work. I don't think my wife would like it.
For example, I have a social life and I'm honestly not that dedicated to this particular search for knowledge.
And if we said, Oh yeah, we're going out to dinner, but this is one of the days I'm randomised not to drink, you know,
now it's not going to work and I thought I'd be even less likely to be able to randomise others to drink or not drink and give
a day's probably much easier to randomise them to drink every day for a given month as the various researchers have done.
Perhaps there's an animal model, I don't know. But like most nutritional risk factors, red wine and glucose is very hard to study.
It's really difficult to study nutritional risk factors apart from anything else.
If you drink red wine, you're not drinking something else. And so this is always the problem.
It's like saying nuts are good for you. Yeah, if you eat lots of nuts, you're not eating that much REM steak.
So, you know, it's very difficult to pin down one factor.
Oh, I've done it again. Now, the study was prospective.
It appears to demonstrate an association, but the sample is rather small.
Just one person can't really get smaller.
And even if this relationship were causal and not associated with other dietary things, you know, might be just an idiosyncratic reaction.
It might be just me or a particular type of type two diabetes I have,
because type two diabetes is a very variable condition and there is some evidence that it's in fact several different diseases.
Perhaps the next step, I thought, would be see how other statistically minded people with type two diabetes.
So get the diabetic statisticians of the world to unite, but only the ones who like red wine.
And to replicate this study.
I thought it might be nice to explore this within my own family, but that can't be done because it's a condition of later life.
Most of the people I know I knew with type two diabetes in my family have died and there's only my sister left that I know of.
And she she prefers white. Perhaps a few statisticians with diabetes might be moved to add to knowledge.
How have the response since my significance article has been known?
Be interesting to see how this works in type one diabetes two, which is a completely different disease.
Ask for myself. I continue to record my blood glucose.
I did it this morning. It was 10.7, quite high.
I've added other data, the type of other alcohol, beer, whisky, white wine, the number of drinks, and some information about food consumption.
How much carbohydrate not measured in a scientific way, but equivalence of a slice of bread.
And approximately whether I exercised on the day before as well, because I have an exercise bike,
I try to go on it most days and of course I'll drink red wine as usual.
It seems to be rather good for me. Oh, okay.
Thank you very much. At the time development in Jeff Aronson and the Significance editorial board for their helpful comments on earlier drafts.
Has anybody ever thanked anybody for their extremely annoying comments on an earlier draft?
They were extremely helpful, all of them. I'd also like to thank my two GP's, Sam Patel, who diagnosed me and Alison Hunter,
who now looks after me for their excellent care, stuffing me full of drugs and keeping it within the bounds of reason.
Thanks.