EPoCH needs you!

Why do we need a research advisory panel?

We want to make sure that EPoCH research findings reach the right people in the right way and we don’t accidentally end up adding to the confusion around health advice during pregnancy.

Therefore, we are setting up a Research Advisory Panel of researchers, policy makers and people with real life experience of giving and receiving pregnancy advice.

What will panel members do?

Panel members will give us feedback on our plans, and tell us how they think we can best communicate our findings in the most appropriate, effective way. In return, we will keep panel members up to date on our findings, and they will be invited to the academic and/or public events that we organise. It’s a great opportunity to get involved with some exciting research from the University of Bristol.

When people sign up to the panel, they will answer a few short questions to get their opinions about EPoCH. We’ll then create a summary of everyone’s responses, which we’ll share with the other panel members. We’ll also explain how we’ve taken their responses on board and how this has affected our future plans.

After this initial survey, we’ll be in touch every time we have some exciting news to share (but we promise not to spam people!). We’ll also send mini reports every six months or so and ask for panel members’ comments and ideas. Occasionally, if panel members agree it would be useful, we might set up teleconferences or face-to-face meetings to discuss further.

How can people join the panel?

If you’re interested in joining the panel, please fill out this short survey.

How might fathers influence the health of their offspring?

A novel thing about EPoCH is that we’re not just focusing on maternal influences on offspring health, we’re looking at paternal influences as well.

One of the reasons that most other studies have focused on maternal factors is that it’s perhaps easier to see how mothers might have an effect on their child’s health. After all, the fetus develops inside the mother’s body for nine months and often continues to be supported by her breastmilk throughout infancy. However, in a new paper from me and Debbie Lawlor published in the journal Diabetologia, we explain that there are lots of ways that fathers might affect their child’s health as well, and appreciating this could have really important implications. The paper focuses on obesity and type two diabetes, but the points we make are relevant to other health traits and diseases as well.

How could fathers influence the health of their children?

These are the main mechanisms we discuss in the paper:

  • Through paternal DNA. A father contributes around half of their child’s DNA, so it’s easy to see how a father’s genetic risk of disease can be transmitted across generations. Furthermore, a father’s environment and behaviour (e.g. smoking) could damage sperm and cause genetic mutations in sperm DNA, which could be passed on to his child.
  • Through “epigenetic” effects in sperm. The term “epigenetics” refers to molecular changes that affect how the body interprets DNA, without any changes occurring to the DNA sequence itself. Some evidence suggests that a father’s environment and lifestyle can cause epigenetic changes in his sperm, that could then be passed on to his child. These epigenetic changes might influence the child’s health and risk of disease.
  • Through a paternal influence on the child after birth. There are lots of ways a father can influence their child’s environment, which can in turn affect the child’s health. This includes things like how often the father looks after the child, his parenting style, his activity levels, what he feeds the child, etc.
  • Through a father’s influence on the child’s mother. During pregnancy, a father can influence a mother’s environment and physiology through things like causing her stress or giving her emotional support. This might have an effect on the fetus developing in her womb. After the birth of the child, a father might influence the type and level of child care a mother is able to provide, which could have a knock-on effect on child health.
There are lots of ways in which fathers might influence the health of their offspring. This figure was originally published in our paper in Diabetologia (rdcu.be/bPCBa).

What does this mean for public health, clinical practice and society?

Appreciating the role of fathers means that fathers could be given advice and support to help improve offspring health, and their own. Currently hardly any advice is offered to fathers-to-be, so this would be an important step forward. Understanding the role of fathers would also help challenge assumptions that mothers are the most important causal factor shaping their children’s health. This could help lessen the blame sometimes placed on mothers for the ill health of the next generation.

What’s the current evidence like?

In the paper, we reviewed all the current literature we could find on paternal effects on offspring risk of obesity and type 2 diabetes. We found that, although there have been about 116 studies, this is far less than the number of studies looking at maternal effects. Also, a lot of these studies just show correlations between paternal factors and offspring health (and correlation does not equal causation!).

What is needed now is a concerted effort to find out how much paternal factors actually causally affect offspring health. This is exactly what EPoCH is trying to do, so watch this space!

What is “Mendelian randomization”?

Mendelian randomisation (with an uppercase ‘M’, a lowercase ‘r’ and an unfortunately Americanised ‘z’) is one of the techniques EPoCH uses to understand whether parents’ lifestyles in the prenatal period causally affect the health of their children.

The technique (which cool kids call ‘MR’) is based on the idea that genetics can tell us about non-genetic factors and their effects on health and disease.

Many of the people I work with at the University of Bristol (most notably the director of the MRC Integrative Epidemiology Unit, George Davey Smith) have championed MR, and over the past decade there has been a huge increase in the number of published MR studies.

To be honest, I struggled with understanding MR when I started working at the University of Bristol. At one early department meeting I asked whether there was “a course or something on MR for Dummies?” Thus charming my new colleagues with my cutesy self-deprecating wit.

And I know it’s not just me, because I have tried to explain MR to multiple confused faces belonging to students, academics, clinicians, members of the public, and, most bemused of all, my friends and family (“WHY is she telling us this?”).

But now that I’m the principal investigator on a grant that includes MR, I want to be able to explain it in a way that other people understand, so here goes…

MR helps us tell the difference between correlation and causation

MR uses the chance (or “random”) distribution of genes in a population to tell us about whether certain non-genetic characteristics or behaviours cause other characteristics or disease. I’ve written more about why distinguishing correlation from causation is important here.

Genetic data as a “proxy”

MR uses genetic information as a “proxy” for non-genetic information. For example, people with a certain variant of the ALDH2 gene (let’s call it variant 1) are much more likely to drink alcohol than people with another variant (let’s call it variant 2). So if we want to study the effects of parents’ alcohol  consumption on offspring birth weight, we can compare the average birth weight in babies of parents with variant 1 to the average in babies of parents with variant 2.

This can give us a better idea of causation than if we just tried to study this by asking parents how much they drink (i.e. if we didn’t use their genetic information).

That’s because genetic information is randomised at conception, so the chance of someone getting variant 1 or variant 2 is random and not affected by any confounding factors. On the other hand, how much alcohol parents drink will be heavily influenced by confounding factors such as how much money they have, where they live, their religion, etc.

Parents might also forget how much alcohol they have consumed, or under-report it, which would introduce reporting bias. Genetic information is measured objectively and therefore not affected by this type of bias.

Also, because genetic variants are assigned at conception and then can’t be changed, there’s no chance that the outcome (birth weight) can influence the exposure (parents’ alcohol intake), so reverse causation is not an issue in MR either.

(…reverse causation is unlikely to be much of an issue in EPoCH anyway, because we know that the exposure (e.g. drinking alcohol during pregnancy) always comes before the outcome (e.g. weight at birth) in this study).

How EPoCH will use MR

In EPoCH, we’ll use MR to study the causal effects of maternal and paternal health behaviours on childhood health. Although there is lots of observational evidence suggesting that parental (particularly maternal) factors are associated with the health of their children, very few studies have looked at whether these associations are causal.

The assumptions of MR

MR can be a really useful tool for “causal inference”, but there are many things to consider before drawing conclusions. In particular, we need to check that the following main “assumptions of MR” are being met.

The relevance assumption

To be suitable for MR, a genetic variant should be very strongly associated with the exposure being studied. So in our example, having variant 1 of ALDH2 must be very strongly associated with drinking more alcohol.

The independence assumption

The genetic variant must not be affected by any of the other factors that affect the outcome, i.e. the association between the genetic variant and the outcome must not be confounded. So smoking (etc) shouldn’t affect the chances of having ALDH2 variant 1 or 2.

The exclusion restriction assumption

The effect of the genetic variant on the outcome should not act via any pathway that doesn’t involve the exposure. So having ALDH2 variant 1 should not affect birth weight through any pathway that doesn’t involve an effect on drinking alcohol. E.g. ALDH2 variant 1 should not affect how much a person smokes, because this might then have a causal effect on offspring birth weight independently of any effect of alcohol consumption.

How can we be sure MR is giving us the right answer?

Neil Davies, Michael Holmes and George Davey Smith have written an excellent introduction to MR that outlines how we can check that the assumptions of MR are being met. We’ll be doing all we can in EPoCH to check these assumptions. However, even with multiple checks, it will be difficult to tell that an answer is “right” using MR alone.

That’s why we’re combining MR with other causal inference techniques, such as sibling comparisons and negative control designs, to “triangulate” the evidence. If all these different strands of evidence point towards the same answer, then that will strengthen our confidence that the answer is correct.

A two minute explainer

Well that was my attempt to explain MR, but if you’re still confused, George manages to explain it much more eloquently in just two minutes in the following animation…

(I probably should’ve just posted this and saved everyone’s time… soz).

Ten weeks in Oslo before EPoCH kicks off…

Although the EPoCH blog will mostly be about plans, activities and findings directly related to the EPoCH project, I also want to use it to give a bit of an insight into our other activities (and when I say “our”, I currently mean “my”, until I find someone to help me…).

I recently spent 10 weeks visiting the Centre for Fertility and Health at the Norwegian Institute for Public Health in Oslo. I was really lucky to get a Gro Harlem Brundtland scholarship from the Centre, which funded my stay.

So I thought I’d share my reflections on an experience that will undoubtedly influence how I approach the EPoCH project now that it has officially started (eek!).

The first thing to say is…

Oslo is awesome…

I really enjoyed being in Oslo. The Centre for Fertility and Health is housed in this brutalist concrete block above a bike shop and a music shop. If you really like concrete, wood and brass staircases (and, it turns out, I really do), this place is for you. I don’t know how to make this not sound sarcastic, but I genuinely love this building.

I sat above the sign that says “Birk“.

Here’s a list of all the things I was working on while I was there:

  • I put together a couple of project ideas (one using maternal epigenetics to predict adverse pregnancy outcomes, and one using a qualitative research method to identify the needs and challenges faced by pregnant couples).
  • I started to think more clearly about another couple of early ideas (one around rising trends in age at first birth, and one around the impact of climate change on fertility and health).
  • I carried out research using UK survey data to explore reproductive “intentions” in teenagers (i.e., what factors are associated with teenagers’ intentions to have or not have children, and the age at which they say they want to start a family).
  • I applied for ethical approval to access Norwegian data (from the MoBa cohort) for the EPoCH study.
  • I advertised for a new position as a (senior) research associate on the EPoCH study.
  • I made a short animation to explain EPoCH.
  • I started planning the EPoCH research advisory panel.
  • I read the first draft of a collaborator’s new book on maternal effects (and visited this collaborator in Berlin).
  • I wrote a couple of papers I’d started working on in Bristol (a large study on paternal BMI and offspring methylation, and a review of paternal impacts on offspring risk of obesity and type 2 diabetes).
  • I collaborated (remotely!) with artist Olga Trevisan to create a piece of art based on my research for the Creative Reactions exhibition (more on this soon).
  • I supervised my PhD student (Laura) while she is on her own academic visit to Rotterdam.
  • I reviewed abstracts for the Developmental Origins of Health and Disease (DOHaD) conference later this year.
  • I planned lectures for a couple of courses coming up in the Summer.
  • I helped organise a teaching team and planned content for a unit on molecular epidemiology as part of Bristol’s new MSc in Epidemiology.
  • I marked students’ work from two undergraduate courses I teach back in Bristol.
  • I took one week out to come back to Bristol to teach a short course on Epigenetic Epidemiology and celebrate my first PhD student, Dr(!!) Diana Juvinao Quintero, passing her viva.
The beautiful view from my living room when I first arrived in early-March.

And here’s a list of all the things I got up to outside of work:

  • I marvelled at the beautiful ever-changing view from my apartment as Oslo went from being covered in bright white, deep, compacted snow to being all shades of green and warm (24 degrees!). I could have watch it all day. I miss it.
  • I walked down the river from my apartment into town, noticing how nearly all Norwegians look impressively healthy and wholesome and also know how to quietly enjoy a river (my favourite type of person is quiet). Also at least half of the prams were being pushed by men (!!).
  • I spent time with some lovely Norwegian people, most notably Maria and Ellen, who I enjoyed many (very healthy) lunches with. I miss them! (The lunches and the people.)
  • I caught buses and trams all over Oslo… I love an efficient tram system 🙂
  • I walked on the roof of the opera house (the only opera house I’ve ever walked on the roof of).
  • I enjoyed a two hour sightseeing boat tour of the Oslo fjord.
  • I saw Bristol-born New Zealand-raised Tiny Ruins (supported by a woman with hand pumped harmonium) play at a lovely venue I’ve forgotten the name of.
  • I visited a flea market in Grünerløkka school.
  • I drank a lovely glass of red wine looking across the harbour from the seats outside Salt (a sort of giant communal sauna… which sounds like a nightmare, but it was ok because you could also just have a drink with all your clothes on). Sauna-aside, Salt is the most “Bristol” thing I found in Oslo (I’m not advocating they should put a giant communal sauna in Stokes Croft).
  • I drank a lovely refreshing Aperol spritz from the terrace of the restaurant in Ekebergparken, with an impressive view of the city.
  • I walked through the forest in Ekebergparken (twice… because it was so amazingly beautiful there).
  • I caught the Holmenkollen line train up to Frognerseteren and walked around a bit (again, twice because it’s so beautiful). The train ride alone is a big part of its charm.
  • I saw some art that I liked at the Astrup Fearnley Museum of Modern Art.
  • I fed a rabbit a dandelion at the Norwegian Museum of Cultural History.
  • I caught a boat to and then walked around Bygdøy.
  • I went shopping in Majorstuen.
  • I ate delicious cupcakes in Mathallen (a food hall… I think that’s even the literal translation).
  • I watched a LOT of the only English-speaking TV programmes I’ve found on TV (British quiz show Pointless and American sitcom Modern Family). Seriously, I must never watch these programmes again. It has been too much.
  • I developed an obsession with peanut butter on Wasa crisp breads… You’d think crisp breads would be much of a muchness, but Ryvitas are nowhere near as good as these things.
  • I ran (for less than three minutes) in one of the world’s biggest relay races with a team from the institute where I was working. This was really fun and in hindsight didn’t warrant the stress I put myself through worrying about being really slow or falling over… (I was really slow, but I didn’t fall over, so I’m marking that up as a success).
  • I got a ferry to an island for a tour and a lovely meal during the Centre annual symposium. It was nice to catch up with people from Bristol since they were visiting too.
  • I celebrated Norwegian constitution day by watching the parade, going to a streetfood hall, then catching the train out of Oslo to visit a colleague and her husband on her lovely farm (where I met two cats, two rabbits, two horses and got to look around an amazing museum of old radio and TV-related technology).
Wine + sun + just been on a boat = half a smile

…But it helped remind me that home is pretty good too

The view from my house when the weather is being characteristically confusing.

I managed to get up to quite a lot while I was in Oslo, both in and out of work, but the thing I valued most was the opportunity to step back from the day-to-day firefighting of academia and think more deeply and clearly about my research and my approach to my work, and I guess my non-work, life.

It was so nice to have time and space to think. Away from all the other competing commitments. I had so many ideas (of varying quality, obviously), and I was able to read and write about them instead of just burying them because I’ve got to reformat my CV or review five papers or whatever… It helped remind me why I really like my job. And now I’m back in Bristol I feel pretty refreshed and really excited to get started on the EPoCH project.

It’s funny because (as anyone who spoke to me in the weeks leading up to the visit will attest) I was really apprehensive about being away from home for so long. I love my family and friends and Bristol and my new (slightly shambolic, slightly falling down a hill, slightly in need of a complete rewiring) house and my lovely strange little cat, Alan. But, I really surprised myself at how “okay” I was. I even occasionally felt like I was thriving away from home. Which isn’t to say I wasn’t really looking forward to coming back, but it made me realise that my love for “home comforts” is still on the right side of healthy… So that’s good 🙂

If I ever get the opportunity to do something similar again, I’m jumping on it.

TL;DR

I’m really glad I went to Oslo for ten weeks.

Oslo fjord. Sitting outside the Astrup Fearnley Museum of Modern Art in the blazing sunshine. Not pictured: there were squashed tomatoes all over the floor.

We’re hiring!

Although I often use “we” when referring to the EPoCH team, it’s in the royal sense, as it’s very much just “me” currently.

I would like to change that though. So I’m advertising for a research associate or senior research associate to come and help me out.

Follow the link to learn more:  https://www.jobs.ac.uk/job/BRM274/research-associate-or-senior-research-associate-in-genetic-epidemiology-mrc-integrative-epidemiology-unit-ieu

And feel free to get in touch for an informal chat about the role.

The deadline for applications is the 12th of May 2019.

New paper!

Imbalance in the scientific literature

In a new paper published in the Journal of Developmental Origins of Health and Disease, Debbie Lawlor, Sarah Richardson, Laura Schellhas and I show that there have been more studies of maternal prenatal influences on offspring health than any other factors.

We took all the studies that have been published in the journal since it began nearly a decade ago and categorised them based on the things they studied.  You can visualise the results here.

Assumptions about the “causal primacy” of maternal pregnancy effects

This work builds on an article we wrote last year where we argue that this focus on maternal pregnancy effects has come about because people assume that mothers are the single most important factor in shaping a child’s health.

But is this assumption true? You can read more in a blog I wrote earlier this year for WRISK (spoiler: I don’t think it is).

It’s the mother! Is there a strong scientific rationale for studying pregnant mothers so intensively?

Why is this a problem?

This assumption, and the resulting imbalanced research, means that we might be missing other factors that could be easier to change to improve child health. For example, paternal or postnatal factors might lessen or increase the effect of any maternal or pregnancy factor, or might be important factors independently of maternal exposures.

Although well-meaning, complex scientific findings about maternal effects are being used to provide simplified health advice to women about what they should and shouldn’t do during pregnancy. This feeds into public beliefs about how pregnant women should behave, which can limit their freedom and negatively affect their experience of pregnancy and parenting.

What are we doing about it?

To create more of a balance, in our paper we call for more research on how child health might be influenced by fathers and other factors, including the social conditions and inequalities that influence health behaviours. We also call for greater attention to be paid to how health advice to pregnant women is constructed and conveyed, with clear communication of the supporting scientific evidence to allow individuals to form their own opinions.

By studying maternal AND paternal factors, the EPoCH study will help highlight whether attempts to improve child health are best targeted at mothers, fathers or both parents. We’ll work closely with organisations like WRISK to ensure our results are communicated effectively and sensitively to avoid blaming parents.

 

Why correlation does not equal causation

One of the main aims of EPoCH is to understand whether parents’ lifestyles in the prenatal period causally affect the health of their children. The project will use several techniques to try to tease apart correlation from causation. In our first blog post, I’m going to try to explain why correlation does not equal causation and why we often need to separate the two.

Example: does drinking a small amount of alcohol every day reduce your chance of developing heart disease?

We might see in the news that a study finds that people who drink a small amount of alcohol every day have lower rates of coronary heart disease than people who don’t drink at all (in fact, here are a few examples of news articles along these lines). The article might then say that this means we can all reduce our risk of heart disease by enjoying a lovely drop of booze every day.

Observational evidence

More often than not, these sorts of studies are based on “observational evidence”, i.e. evidence that has been gathered by observing a group of people enrolled in either a “cohort” or a “case-control” study. There is no experiment, the researchers haven’t changed anything, and the people taking part in the study haven’t received any treatment or intervention. Instead, the researchers have compared the rate of heart disease in people who say they drink a little and people who say they don’t drink, and they have observed that, proportionally, more people who don’t drink have heart disease.

All of the studies used in EPoCH are observational studies. They are birth cohorts that enrol mothers, partners and children at the time of pregnancy or the child’s birth and then observe them over time (not in a creepy way, but with their full consent, using questionnaires and interviews, etc). So, it’s really important that we are aware of the different interpretations of observational evidence.

Potential interpretations of observational evidence

In the alcohol-heart disease example, let’s think of possible reasons why people who drink small amounts of alcohol might have a lower risk of heart disease:

1. Drinking small amounts of alcohol reduces the chance of getting heart disease.

This is the explanation the news article has homed in on (although, without further evidence, there is no reason to believe this explanation over the others below). It suggests that drinking alcohol causes lower risk of heart disease, i.e. there is a true causal effect from alcohol –> lower heart disease.

2. Having heart disease makes people give up drinking.

This isn’t as enticing at the first explanation, because it doesn’t mean we can all indulge in our penchant for Babycham on a nightly basis, but without further evidence, it is equally likely. In fact, given what we already know (from other studies) about alcohol generally being bad for us, we can assume that this explanation is more likely. Most people who drink probably change their drinking habits if they find out they’ve got heart disease. They might give up completely. They might even be in hospital, where alcohol is not available. This is an example of reverse causation, i.e. the direction of causal effect is from lower heart disease –> alcohol.

For EPoCH, where we’re interested in prenatal influences on childhood health, reverse causation is less likely. For example, a child’s IQ at age 7 can’t feasibly affect whether the child’s father drank coffee before they were born. In fancier words, the temporal order of events makes reverse causation impossible.

3. People who drink a small amounts of alcohol have something else about them that reduces their chance of getting heart disease, and it’s that thing (not the alcohol) that’s responsible for the link.

The “something else about them” could be anything, but say for example that people who drink small amounts of alcohol are wealthier than people who don’t. If this is true, then wealth affects both alcohol and risk of heart disease, thereby creating a false or a stronger relationship between those two factors. If we imagine that many of the people who are drinking a small amount of alcohol every day are middle class people drinking a glass of wine with their dinner, then we might imagine that these people can also afford a high quality diet, better access to health care and many of the other health advantages to having a higher socioeconomic position. So it makes sense that, in addition to being more likely to drink in moderation, wealthy people might be less likely to have heart disease. In this case, the relationship between alcohol and heart disease would be explained partly, or even completely, by the differences in wealth between the two groups. This is an example of “confounding” (where the confounder in this example is wealth), i.e. higher wealth –> alcohol, and, higher wealth –> lower heart disease, with no (or a weaker-than-estimated) direct causal effect between alcohol and heart disease in either direction.

4. Drinking small amounts of alcohol is not related to having a lower risk of heart disease in the general population, but it appears to be in this study because of bias.

There are lots of types of bias that can distort the results of a study so that they don’t match up with what we would see if we had perfect data on the whole population. One example is reporting bias whereby participants in the study misreport their behaviour (for example, because they can’t remember, or because they feel uncomfortable reporting the truth). In this case, people with heart disease might say they don’t drink because they have been told by a doctor that they should limit their alcohol intake and they want to give the “right” answer, even though, in reality, they do drink. Another example is loss-to-follow-up bias whereby participants die or drop out of the study because of the thing being studied before all of their data can be collected. In this case, drinking a little may in fact cause people to either die or drop out of the study before they are recorded as having heart disease. Therefore the group that doesn’t drink will be left with a higher proportion of people with heart disease than the group that drinks small amounts. In both these examples, bias would distort the numbers to make it appear like people who don’t drink have a higher risk of heart disease than those that drink a small amount (i.e. the results of the observational study).

5. Drinking small amounts of alcohol is not related to having a lower risk of heart disease in the general population, but it appears to be in this study because of chance.

Because the study is based on just a sample of people, the researchers might have found a fluke association that they wouldn’t find if they were to re-run their study using a different sample, or using everyone in the population. The researchers will have tried to rule out this explanation by conducting statistical tests that give a measure of “precision” (i.e. P-values and confidence intervals), but chance findings can never be ruled out completely.

So correlation does not imply causation… but why do we care?

The news article’s claim that drinking alcohol can slash the risk of heart disease (i.e. the interpretation of the observational evidence as evidence of explanation 1 – a true causal effect) is a classic example of taking correlative evidence and making causative claims, i.e. confusing correlation and causation.

But why is it important to know whether something causes a disease or is merely correlated?

The clue is in the way the news article has framed the evidence, i.e. that we can all reduce our risk of heart disease by drinking alcohol every day. Identifying causal relationships helps us identify things we can modify to improve our health. If there was a lot of strong causal evidence that drinking a small amount every day really does reduce our risk of heart disease, then doctors would start prescribing alcohol.

What will EPoCH do?

A lot of the current health advice given to parents (mostly mums) is based on correlative rather than causative findings from observational studies, so we desperately need better, causal evidence to support this advice.

In EPoCH, we’ll use statistical techniques to try to tease apart correlation from causation. We’ll also work with the media and groups like WRISK to help make sure our findings are interpreted accurately by journalists, policy makers, healthcare professionals and ultimately parents.

You can find out more about our plansmethods and results by exploring our blog.