Waching daily Jan 2 2019

MODERATOR: Welcome and thank you for joining us today for the November 2018 Precision Medicine

and Population Health Webinar.

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I also wanted to note that today's webinar is being recorded and will be posted online

at a later date.

And with that I'd like to pass it over to Debbie Winn who will introduce our speaker.

DEBBIE WINN: Thank you very much.

We're delighted to have today Professor George Davey Smith from the University of

Bristol in the UK.

He's a clinical epidemiologist whose research has pioneered understanding of the causes

and alleviation of health inequalities, life course epidemiology, systematic reviewing

of evidence of effectiveness of health care and health care policy interventions and population

health contributions to the new genetics.

He's published over a thousand peer review journals and 15 books in edited collections.

He is co-editor of the International Journal of Epi and during his tenure the impact factor

has increased from less than two to over nine, which is terrific.

He's been established his potential to the running of a large number of epidemiologic

cohort studies evolving detailed clinical and biomarker assessments.

Currently he's Director of the Avon Longitudinal Study of Parents and Children and he is the

Director of the Medical Research Council Center for Causal Analyses and Translational Epidemiology

as well as the integrative epidemiology unit.

He is Director of the Welcome Trust Four Year PhD Program and Life Course in Genetic Epidemiology

at the School of Social and Community Medicine, University of Bristol.

So, we are really pleased to have him today.

He will be talking about what is Mendelian randomization and how it can better used as

a tool for medicine and public health opportunities and challenges.

He'll be using examples from cancer cardiovascular diseases and other fields to illustrate this

approach.

So, thank you very much Dr. Smith for being here and please go ahead.

GEORGE DAVEY SMITH: That's great.

Thank you indeed for the invitation to present this webinar and thanks for the kind introduction.

I'm sort of clearly nearing retirement phase because many of those things you read out

I've ceased to do.

So, I stopped a year or two ago being the co-editor in the International Journal of

Epidemiology and Nick Timpson is now the Director of the Avon Longitudinal Study of Parents

and Children.

And we changed the name of our center.

It was CAITE, C-A-I-T-E was the abbreviation, but when we actually Googled that that meant

you were not good and worn out in Gaelic.

So, we are now the MRC Integrative Epidemiology Unit.

So, I'll just say thanks again for this invitation.

I'm going to talk briefly.

Well, not that briefly.

About 40 minutes or less of Mendelian randomization.

And then it will be questions and answers hopefully.

So, this is just the outline of the talk I'm going to give.

I'm going to give a brief introduction to MR and then describe the instrumental variables

assumptions that are necessary for interpreting Mendelian randomization studies.

A series of sensitivity analyses and ways of checking the assumptions or at least doing

sensitivity analyses assumptions.

And finish on describing or discussing Mendelian randomization when you're looking at disease

liability.

So, I'm starting with a schema of conventional observational epidemiology where you measure

your modifiable exposure, for example, cholesterol levels or seriatric (ph.) protein.

That's sort of factor of behavior, smoking or consumption, physical activity.

You measure that in a large group of people and then follow them up and relate the exposure

to the outcome, for example, coronary heart disease.

But when examining this relationship there are of course many confounders that could

come into play, factors that influence both the exposure and the outcome and leads to

an association between the two, which is non-causal.

So, for example, smoking increases the levels of seriatric protein and also increases the

risk of coronary heart disease and would confound the association of seriatric protein and coronary

heart disease.

Or secondly you could have reverse causation and that would be that the disease process,

for example, arthrosclerosis, which leads to coronary heart disease, the disease first

influences the exposure, so arthrosclerosis is an inflammatory condition and would increase

the active protein.

And that then would lead to the association between the two including a prospective association,

which is due to actually early stages of the outcome influencing the exposure.

That would be reverse causation.

So, the trick in Mendelian randomization is to take what is called an instrumental variable.

This is something which reliably associates with your exposure, but will not suffer from

the confounding or the reverse causation that you see in a conventional observational study.

So genetic variance can serve as such instrumental variables.

So, consider genetic variance which are reliably associated with LDL cholesterol levels.

The genetic variance will not in general be confounded by the socioeconomic pace or lifestyle

physiological factors which would confound the conventional association.

And second obviously the disease process cannot influence your gene line, genetic variance.

The variance you received at conception.

So, there's no reverse causation and generally there is no confounding.

Thus, the instrumental variable or the genetic variance can serve as a proxy.

So, the observation association is often impossible to exclude confounding or reverse causation,

but the genetic variant will not suffer from the confounding or the reverse causation that

the measured risk factor, the measured exposure or cholesterol level here, for example, would

suffer from.

So, in this set up if you examine the association of the instrumental variable, the genetic

variant with your outcome, coronary heart disease, with the association of the instrumental

variable with cholesterol level, and indeed you divide the first, the association with

the outcome by the association with the cholesterol, with cholesterol levels, this allows you to

estimate the causal effect of the exposure, in this case LDL cholesterol with coronary

heart disease.

Now the Mendelian randomization aspect of this set up, this is a straightforward sort

of instrumental variable analysis, but the Mendelian randomization aspect, and if you

don't make this interpretation then in my view you're not performing a Mendelian randomization

study, although people use the terminology when they are not aiming to make, to infer

cause for modifiable exposure.

The Mendelian randomization aspect you are considering that the modifiable exposure,

the effects of the modifiable exposure on the outcome will be the same whether the modifiable

exposure is influenced by environmentally changeable factors, such as diet, use of cholesterol

lowering medication, etc. as when it is influenced by genotype.

So that is the absolutely key assumption is that the effect of the exposure on the outcome

will be the same whether the exposure is influenced by modifiable factors that you can do something

about in the same way as it is influenced by genetic variation.

So, this can be considered to reflect the phenocopy/genocopy dialectic.

So, in the late 1930s Goldschmidt introduced the concept of phenocopy, which is where something

in the environment, for example, your very high temperatures, could lead to a modification

which could also occur through genetic difference.

So that's the notion of phenocopy, i.e., the environment is copying something that

can be produced by genotype.

And Schmalhausen (ph.) around the same time introduced the notion of genocopy, which is

simply the mirror image of phenocopy.

Genocopy is that a genetic variant can mimic the effects of the environment.

So, you can see the two are basically saying the same thing, it's just whether you're

looking at it from the phonotypic end or the genotypic end.

So, we can consider sort of a classic example of this, which is Hartnup's syndrome, which

is induced by genotype, but the disease looks like pellagra and pellagra is induced by niacin

deficiency.

Now the mutation in Hartnup's syndrome is in a gene which is related to niacin.

And so, if in the 1950s Hartnup's syndrome was identified and seen to look like pellagra,

if it hadn't been realized that a niacin deficiency was the cause of pellagra that

genotypic association would have given the same information.

So Hartnup's syndrome is a genetic syndrome, can be considered a genocopy of pellagra or

pellagra can be considered a phenocopy of Hartnup's syndrome.

So that's the important interpretive factor.

And I'll go back to this slide, the only one thing you remembered, than this would

be it, is that you must making this assumption that the modifiable exposure, however it is

influenced, is having the same effect on the outcome.

And that's how you can use the genotype to infer something about how modification

of exposures will change disease risk.

So, this is common place in developmental genetics, the notion of gene environment equivalence

of gene environment interchangeability that Mary West Eberhard, for example, discusses

at length, this notion that gene expression has changed, it will have the same impact

whether it's changed by a genetic difference or by an environmental influence.

It's a nice quote from Zuckerkandl and Villet that no doubt all environmental effects can

be mimicked by one or several mutations.

I think that's maybe slight overstatement.

I mean, I think being hit by a bus, probably can't be mimicked by mutations, but many

of the things that we're interested in preventative medicine, for example, can be mimicked by

genetic variation.

So just one example here of Mendelian randomization.

And this is in the examination of selenium and prostate cancer risk.

And then here we see the Mendelian randomization occurs so the dice being thrown and that's

the genetic variance inherited independently of each other.

Mendelian law of independence assortment and of environmental factors which relates to

the little segregation, at least of environmental factors acting before birth, before conception

and then before birth.

So, the genetic variance serves as instrumental variable to the modifiable exposure which

is selenium and the observational studies those selenium levels or selenium intake will

be confounded and then maybe reverse causation or perhaps the early stages of prostate cancer

influence your selenium levels.

So, there was a substantial amount of epidemiological and other evidence that suggested that selenium

protected against prostate cancer risk.

Indeed, this evidence was considered substantial enough to launch a large scale randomized

controlled trial, which is called the select trial.

So, on the left we see the RCT where the randomization method, randomized people either to a placebo

or to selenium supplementation, which increased plasma selenium levels.

On the right-hand side, we see the Mendelian randomization equivalent.

Of course, the randomization there is at conception so it's likely that from soon after conception

on it is likely that the fetus and then the adult would be exposed to different levels

of selenium.

So, this is an important thing to bear in mind when I discuss the interpretation of

the instrumental variables estimates.

But after the randomized control trial if you randomize by genotype you're carrying

out the equivalent of an intention to treat analysis.

You don't take into account what the actual selenium levels are in folk, you analyze by

genotype, just as in randomized control trial your intention to treat analysis is by what

they were originally randomized to, not what their selenium levels are.

So, in the select trial despite the sort of substantial evidence there was from observational

studies, the randomization to selenium supplementation did not product prostate cancer risk and that

was in the trail.

And then in Mendelian randomization study using 22,000 cases and 22,000 controls in

the practical consortium scaling up the effect of subtle genetic variance that relate to

selenium levels and scaling is up to the difference in selenium levels that were induced by randomization

to the supplement, one gets a closely similar estimate and closely similar precision to

the randomized control trial.

And it was a select trial was said to cost around 100 million dollars to carry out and

the question that it would be nice to know the answer to the question would the select

trial be launched today with these Mendelian randomization data suggesting that sustained

differences in selenium levels not leading to a reduction in prostate cancer.

And indeed, sort of the basic principle of Mendelian randomization was considered to

be simple enough to be understood by pregnant women attending anti-natal clinics in the

late 60s and early 1970s.

Here's the front of a leaflet advising about the inheritance of hemophilia on the pregnant

woman there who looks scarily like Margaret Thatcher.

She has here either two possible daughters and two possible sons and beautifully you

actually see the dice being rolled, just as we saw in the previous slide.

This is Mendelian randomization in action.

The carrier mother with one hemophilia carrier in x chromosome will not be suffering from

the condition, but of her daughter's one in two of her daughters would be carriers.

They would also carry the chromosome.

And one of two of her sons would suffer from the condition hemophilia.

So, there's Mendelian randomization in action.

Now if you followed up these two daughters and thousands more of these daughters, you

would be able to compare those with the phenotype, this is influenced by the hemophilia chromosome,

hemophilia carrying chromosome versus the control with the non-hemophilia carrying chromosome.

Now women who carry hemophilia are relatively anti-coagulated, I mean, they don't suffer

from the clinical condition, but on average they are relatively anti-coagulated.

And if you did follow up these girls then what you would see is the ones who are carriers

have a quite substantially lower risk of carrying heart disease.

And now we actually, you know, we know from their trials drugs which lead to relative

anti-coagulation that this reduces the risk of coronary heart disease.

If we didn't have that evidence then this would provide evidence to support that notion,

because the course that girls don't differ in any systematic way by anything other than

their carriage of that particular chromosome.

They don't differ in other ways.

Indeed, they look pretty identical.

So, the look as though they don't have any confounding differences between them, and

indeed they wouldn't.

So, a couple of studies have done precisely that.

And as I say have looked at the risk of coronary heart disease in carriers versus non-carriers

and found that difference.

And getting around to randomization today is often carried out using the two-sample

approach.

And the two-sample approach you obtain genetic variance that relates to the exposure from

GWAS and then you look at a GWAS for the outcome and what is meant to be a similar population

in terms of ancestry, etc., the way you have genetic data on how the genetic variance relates

to the outcome and from that you can infer or calculate the supposed causal effect of

the exposure.

Two sample Mendelian randomization allows Mendelian randomization to be carried out

at home as it were using platforms like MR base and does render it a quite simple way

of obtaining some evidence.

Now the assumptions that you need to make in a Mendelian randomization study can be

the same as the instrumental variable's assumption because that the analysis you're

carrying out.

The first assumption or the relevance assumption is that the genetic variant is reliably associated

with the exposure.

This is the only one of the assumptions you can actually test, do a statistical test of

whether the instrumental variance does indeed relate to your exposure.

The second assumption is that the genetic variance is independent of confounders or

in epidemiological terminology exchangeability so that the greeps defined by genotype do

no differ by confounding factors.

And population stratification would be a major potential cause of confounding here, which

can be dealt with in the ways that population stratification is dealt with genome wide studies,

etc.

The third assumption is that the genetic variant only influences the outcome through the exposure.

So, the genetic variance does not have an effect on the outcome other than one that

is mediated through the exposure.

And that's called the exclusion restriction.

Now IV assumptions two and IV assumptions three cannot be tested.

We quite often occasionally see people who say that they've developed a test for these,

tests for IV2 and IV3 and either they deserve a Nobel Prize or they're wrong.

So far, the latter has sadly been the case.

You can examine how the genetic variance relates to measures of confounders and one would suggest

that that that should be done.

As many measures of confounders that you have.

But, of course, you can never demonstrate, by definition you can't demonstrate associations

without known confounders.

For IV assumption three, we need to see this in the (unint.)

field where instrumental variables came from.

You often see it referred to as here that the genetic variance is independent to the

outcome, while conditional on the exposure X and then the confounders U.

Well, that's something of a heart sink moment because the whole point of Mendelian randomization

is that you don't have measures of the unmeasured confounders by definition.

So how can you examine this if you need to have measures of them?

And, in fact, this statement only becomes true if you actually try to condition on the

exposure X, i.e., if you just do a genotype to outcome association for your exposure you

would just do a genotype to coronary heart disease association for your exposure then

you might think that that should abolish the association with genotype on coronary heart

disease.

Now there's two reasons why that shouldn't happen.

The first reason is that you will not measure the lifetime long term cholesterol measures

in any feasible observational study.

So, if the ecological factor is long term cholesterol level, then you will not be taking

this into account by adjusting to the measures you have in an observation study.

They'll be residual effects of the genotype on the outcome.

And the second, and even sadder thing is that if you do adjust for the exposure for the

X variable in this PowerPoint then that is equivalent to adjusting for a colida (ph.),

adjusting for a colida is when you adjust for something which is influenced by more

than one factor, like by exposure of interest and the measure of confounders in this schematic.

When you adjust for that factor you then induce an association, you induce an association

between the genotype and confounder.

When there is no such confounding in the source population once you do the adjustment, you

induce such confounders.

So not only does it not work it actually makes the situation worse, adjusting for the mediating

factor.

And indeed, these supposed tests for the exclusion restriction often boil down to a performing

such an adjustment.

So, if there is one thing to remember from this webinar it's do not condition on the

intermediate phenotype.

This is probably one of the major issues with Mendelian randomization studies that are published

is that this is attempt … And actually, I care a lot about Mendelian randomization,

so I'll say please do not condition on the intermediate phenotype.

Those of you who are used to mediation analyses, for example, you would instantly recognize

that the schematic I drew is simply a schematic for complete mediation.

It's like the same thing.

You're saying that the effects of the genotype on the outcome are completely mediated by

X.

So, the analyses are the same as if you were trying to just do a conventional mediation

analysis.

And this is why adjusting for a mediator doesn't work as a way of doing mediation analysis.

You induce colida bias and you leave residual effects.

So those are the three, the main three IV assumptions.

You sometimes see people discuss the fourth IV assumptions.

And this is an assumption which is required if you're going to generate IV effect testaments.

I said earlier that you could divide the genotype coronary heart disease association by the

genotype cholesterol association.

And that will give you some estimates of the causal effect of cholesterol on coronary heart

disease.

But the issue is who does that causal effect apply to?

So, we tend to think that it would apply, it would be an average population effect.

Now that would be the case if you accept IV assumption four, which is that there is homogeneity

of exposure effect on the outcome.

So, cholesterol to outcome effect is the same in everyone.

Now you know at the limits of course that's implausible if that's the case, though it's

likely to be some actuality.

The issue is how much, how unreasonable is that assumption?

That would allow you to estimate now for the exposure effect on everyone.

A different assumption would be the monotonicity assumption and that is that is that the genetic

variant leads to a higher level of cholesterol in everyone or no change in cholesterol level.

If an account factual situation could actually change the variant it could crisper people

or whatever.

There's no people who the cholesterol level would go down if they would change from the

high to the low cholesterol variant.

If you assume monotonicity the effects all range in a positive direction from the null

then you can compute what's in the sort of randomized control trials and other incidental

variables is called a complier average exposure effect, i.e., the effect in people where the

genetic variant hasn't indeed influenced the exposure.

Or a third assumption can be made is there's no interaction between your genotype and the

confounders with respect to influencing your exposure.

So, these allow you to make some formed of IV estimates that can be applied to some part

of the population.

So, the worrying thing is that these can't be tested, these IV four assumptions cannot

be tested.

And this has led some I think rather over enthusiastic critics of Mendelian randomization

to state that the effect estimation in the Mendelian randomization is extremely highly

problematic, horribly invalid.

Even though you can't test it, you can interrogate the degree to which it appears to be a problem.

And you can do this by looking at the variance of your outcome in relation to the different

levels of your genetic variant, your different levels of your instrument, because violation

of any of those three components, the homogeneity, monotonicity or the no interaction.

All of them would lead to a variance increase, an increase in the variance in one level of

instrument compared to another level of an instrument.

There would be a difference in variance if this was the case, whatever you consider to

be the treatment allele.

Unless there's an utterly implausible complete cross over situation, which is literally,

is utterly implausible.

So, you'd expect to see a variance difference.

So that's good news because we can of course interrogate genotype associations with outcome

or with the exposure, we can look at the variance when those things are continuous.

And then you can then get some notion of the degree to which this assumption is violated.

And this realized, or this is discussed many years ago by RA Fisher.

So, RA Fisher of course is celebrated for introducing randomized control trials.

In fact, his daughter Joan Fisher Box wrote as have other people he modeled, Fisher modeled

the randomized control trial on Mendel's Law of Independent Assortment.

He was absolutely explicit about that in a 1951 lecture.

So Mendelian randomization actually came before randomized control trials.

Randomized control trials are the phenocopy of Mendelian randomization if you like.

But anyway, Fisher was being criticized in a Fisher randomized trails which were in the

agriculture sphere and largely were being criticized by people making the same criticisms

about the heterogeneity of response doesn't allow you to make any sensible interpretation

of who would benefit.

And in a letter to HE Daniels he said this rather beautiful thing, which is that this

point has, I think, received a rather large amount of theoretical attention which is has

chiefly through lack of contact with the practical experimental situation.

I.e., the people who are raising this problem were ones who'd never got close to a randomized

control trial and didn't actually have any sense of how plausible it was as a serious

violation.

And I think the current situation of Mendelian randomization is the folks who are raising

this issue are generally rather distant from actually doing studies.

And certainly, unlike Fisher they haven't realized that you can look at variance differences

as a way of getting some evidence of how extreme the violation is.

And, of course, we have massively wide association studies which allows us now to have power

to really characterize the variance very well.

This is a nice paper by Alex Young, which shows that for FTO there is this small, there

is evaluation of, nothing massive, but there is evidence of some difference in variance

across genotype for many, many other potential exposures of outcomes, this isn't seen.

So, it is possible to interrogate that assumption.

So anyway, so once you get as far as believing you might as well, you can make IV estimates,

then how do you interpret them?

Well, firstly you need to think of all the assumptions, assumptions one to four.

Then you need to think that the Mendelian randomization estimate will be an estimate

of the lifetime exposure effect from the people who get genotypes related to higher cholesterol

will have higher cholesterol from birth probably and arthrosclerosis develops across the lifetime.

So, you'd be looking at like 60 years or something higher cholesterol.

In a randomized trial you just look at lower cholesterol levels at five years and six years

or so.

So, if you have a biological model that is a cumulative effect of cholesterol, which

makes sense because you know at age 18 when Korean and Vietnam War soldiers were autopsied

they already had arthrosclerosis and we could show that in autopsy cases, young autopsy

cases it related to cholesterol level.

So, what you'd expect is a greater effect in doing randomization studies and what you

actually see is about two-and-a-half-fold effect in an MRI study for a given change

in cholesterol in a trail for five years.

So that's really, really helpful, because it helps us know that lowering cholesterol

in relatively early life will produce greater benefit than lowering it later.

The second thing is that the exposure, it might not be accumulative effect, it might

just relate to a particular critical period, for reasons I won't go into at length here,

there is reason to believe that the robust Mendelian randomization finding that higher

Vitamin D levels protect against multiple sclerosis.

That effect may only apply to the period that people receive an EVB infection, which is

essential a prerequisite for developing multiple sclerosis.

And it's the response to EBV infection which is modulated by Vitamin D.

So, giving people Vitamin D after they've received infection often in childhood in adolescence

say, giving it later than that isn't going to be beneficial.

So, the effect may only relate to a critical period whereas your randomization being from

conception goes right the way across both conception and life.

The interpretation relates to the phenotype that your genotype relates to.

So, if your genotype relates to an enzyme, say a fatty acid, relates to that enzyme then

your interpretation has to be to all the factors then influenced by that enzyme being modified.

You see many Mendelian randomization studies that will use sort of fab student (ph.) factors

as an instrument for linolenic acid because that's what you're interested in.

It's related to many other things.

You can't just pick the fact you're interested in and say it's an instrument for that when

it relates to differences in many other things.

So, the interpretation is to the phenotype which is the genotype is the most proximal,

is the most proximal phenotype to factor the genotype influences.

So, the enzyme, for example, in those cases.

May only be interpreted in terms of liability to the exposure not the exposure itself.

And I'll finish on that point, so I'll come back to that.

And then finally in most current studies, in particular two sample Mendelian randomization

studies, generally relates to disease occurrence, not outcome because the genome wide association

studies the one it's using are of disease occurrence, heart attack cases versus controls,

breast cancer cases serve as controls, prostate cancers versus controls, etc.

So, the Mendelian randomization studies are telling you about how to prevent the disease

not how to treat the disease.

So, take lung cancer, for example, the g wide studies of lung cancer, the top variance in

the first three studies was in a nicotine receptive variance which related to heaviness

of smoking.

So, there you go, Mendelian randomization will cost in terms of millions of dollars

as those studies then cost, shows that smoking is indeed a cause of lung cancer.

But of course, once you develop lung cancer, stopping smoking is hardly an effective therapy.

And that might relate to other conditions.

We simply don't know how many conditions are such that factors influencing onset influence

progression and secondary events.

Coronary heart disease, for example, it seems that most of the factors that influence onset

high cholesterol, smoking, high blood pressure, etc., if you modify those after people have

had a first heart attack it lowers the risk for a second event.

So, in some cases the MR studies are telling you about outcome.

But in many cases, we simply don't know if that's the case.

There are certainly cases where very clearly Mendelian randomization studies, an occurrence

do not speak to disease progression, disease development.

And so, if you want to explore treatment of disease through Mendelian randomization you

need to have Mendelian randomization studies of disease progression, starting with people

with cases and then following them on, which has additional complexities which I'm not

going to talk about here, but have been quite extensively written about.

So, we need more Mendelian randomization studies of disease progression if we want to talk

to treatment.

So, with all those problems why generate IV estimates?

Well, the reasons are, there are many reasons, but a few of them are that most of the sensitivity

analyses or extensions of MR analyses depend upon the ratio of the genetic variance to

outcome to the genetic variance to exposure, because that is what you would expect will

be stable across different genetic variance that relates to the exposure and the outcome.

If the studies are not biased, if the genetic variance are all producing an unbiased effect

they will produce the same IV estimate.

So, you need them for the sensitivity analyses.

Second, comparing the IV estimates and what is observed in trials can help inform about

relative immediacy treatment effects.

With cholesterol suggests they're not very immediate, with blood pressure and cardio

vascular events suggesting they might not be quite as long term or the long-term effects

might not be so many times greater than the shorter-term treatment affects you see.

So, it can be very useful for helping us understand that.

And in some cases, of course, for example, using genetic variance in pregnant women that

relate to their smoking behavior in relation to birth outcomes, such as birth weight, you

have a reasonable guess about which period of the exposure is acting.

So, what are the limitations of Mendelian randomization?

Well, first is to introduce confounding through horizontal pleiotropy, which is where our

genetic variance influences the disease outcome through a pathway which is not through your

exposure.

If it's through your exposure, the genetic variance influences BMI which is your exposure

and that influences blood pressure.

That is called vertical pleiotropy and indeed is the essence of Mendelian randomization,

not a violation.

But you need to have horizontal pleiotropy through a separate biological pathway.

You can interrogate this by using multiple genetic variance because how do you have more

and more genetic variance that relates to an exposure and outcome when they predict

the same causal effect?

It becomes decreasingly likely that they could all be having horizontally pleiotropic effects

which perfectly better balance their predictive causal effect to generate the same effect

estimates.

You can now do this, this just shows the degree to which variance related to LDL cholesterol

relate to coronary heart disease is proportional for their effects on LDL cholesterol.

You can now redo this as many more variants, so it becomes rather implausible that they

are all being violated by horizontal pleiotropy.

Our friend in this situation is often just the simple heterogeneity statistic to say

that the heterogeneity between the effects of the different genetic variance, and you

can interrogate the heterogeneity in various ways.

Secondly you can do a series of sensitivity analyses.

Here is one which is what's known as MR-Egger, which allow you to relax assumptions and obtain

estimates with less stringent assumptions.

So, in the MR-Egger case from the previous slide, the slide I go back to here, you see

that you can get an effect estimate simply about any regression through the genetic variant

effect to the exposure on the X and the outcome on the Y axis.

You force that through the origin, the slope of that is your causal effect estimate.

In the MR-Egger setting you simply don't force the line through the origin and that

then means that the intercept is an estimate for unbalanced pleiotropic effect, the degree

to which the pleiotropy balances so the pleiotropy distorts the estimate in one direction over

the other.

And if you don't force the intercept through the origin the slope remains a valid causal

estimate.

You relax the assumptions of no pleiotropy here to the assumption that the strength of

your genetic variance on the exposure, i.e., on cholesterol, does not perfectly correlate

with any horizontal pleiotropy to factor those variables, which is certainly less stringent

but could have caused the (unint.)

agent.

But there are many such approaches, and more are arriving every day, which I've highlighted

here.

It isn't that any one of these approaches is the correct approach.

People sometimes say that there's a correct approach, they tend to say that their approach

is the correct approach.

They all have different sets of assumptions and they all allow relaxation assumptions

in different ways.

The approach would be to run multiple sensitivity analyses and things which remain robust under

multiple sensitivity analyses are the most believable.

You can also interact your genetic variant with an external, another factor and relate

how the genetic variant effect on the exposure is different in different groups to how the

genetic variant effect on the outcome is different in different groups.

And that gives you another sensitivity analyses of an MR study.

It's easiest to show this by an example, which here is alcohol intake on the risk of

cardiovascular disease, for example.

So, as you know whenever studies are reported of saying alcohol is good for you, it reduces

cardiovascular risk they get much attention.

Here is a recent study in Britain that said that drinking alcohol reduced cardiovascular

risk.

In the newspapers it got very widely covered.

Moderate drinking can lower risk of heart attacks.

This study at Guardian, a sort of high end paper in Britain, going slightly down market

drinking a pint of beer a day linked to reduced risk of heart attacks.

Further down-market Cheers!

Drinkers who have one glass of wine a night are of less risk of heart failure than teetotalers.

Right down to the gutter of our press, the Daily Star, here you see drinking alcohol

slashes risk of heart problems – if you drink this much per week.

In the U.S. of course Time was very sober, alcohol is good for your heart, most of the

time.

And in the Irish Times, a good headline, moderate drinking may cut risk of heart disease.

But I liked this thing here, that moderate drinking may be okay for heart disease but

even heavy drinking … sorry … even heavy drinking may be good for your health.

That was in the Irish Times.

Anyway, a Mendelian randomization study, I've only got a couple of minutes left so I'll

go through this quite quickly.

In cartoon form when you drink alcohol it's metabolized by alcohol dehydrogenate acetaldehyde

and cleared by acetaldehyde dehydrogenates to acetic acid and acetaldehyde gives you

the pleasant effects of alcohol flushing, headache, palpitations, etc.

And in East Asian populations, China, Japan, Korea, Vietnam, etc., people carry, many people

carry a knockout of this genotype and the homozygotes with the knockout drinking alcohol

becomes extremely unpleasant due to flushing and palpitations, etc.

The heterozygotes drink an intermediate amount and the heterozygote wild type do most.

Not so much amongst the men, but you'll see when these studies were carried out, this

is an old analysis, but now huge studies show the same thing.

In these populations women weren't drinking whatever their genotype.

So, this gives us a rather nice no relevance point or a negative control, which is in the

women genotype is not related to alcohol, but the horizontally pleiotropic effects of

the genotype would be expected to remain.

So, if those pleiotropy you would see, and it's not alcohol which has an effect, you

would see the same effects of genotype in men and women.

But if alcohol is generating the association and therefore alcohol is identified as a causal

modifiable factor, you'd see effects in men but not women.

And this is what you see and as you see now huge studies have shown precisely the same

thing, including with stroke risk and other disease outcomes, which is that the men who

are homozygote knockout and drink no alcohol have considerably lower blood pressure than

the men who are heterozygote or homozygote can drink more alcohol.

But in women it would demonstrate the same pleiotropic effects nothing you've seen.

So, this provides evidence against pleiotropy.

And indeed, you can use, if you have multiple groups where there is a different level of

exposure association with a genotype with a much smaller effect or a much large effect

you can estimate the causal effect by regression which is not through the origin.

The intercept is again an estimate of unbalanced, of pleiotropy.

But the slope remains an estimate of the causal effect to using this demonstrates that causal

effect to alcohol on blood pressure.

And alcohol raises HDL cholesterol but lowers LDL cholesterol, which has been shown in other

designs, including trials in many cases.

So, this is a way of using genotype by exogenous factors, it's preferably exogenous factors

such as in this example, which can influence by genotype.

A genotype effect modifier interaction can be used for effect estimation.

And is another sensitivity analyses.

So, I'm going to finish very quickly refer discussing what we'll often see which are

Mendelian randomization studies of a disease where the disease is the exposure and then

you try to say what's the effect of the disease.

And here's a recent paper, which is the most recent one, so I'll show it that I

saw, where it's saying that it's claiming to demonstrate a causal inference of schizophrenia.

This is the exposure on cannabis use.

So, the interpretation here is that the disease is causing cannabis use.

But actually, when you're doing Mendelian randomization, especially if you're doing

it in a two-sample setting, but in a one sample setting unless you've actually measured

when the disease occurs, and events after it's occurred, which isn't the usual situation,

you weren't actually looking at the effects of the disease you are looking at the effects

of the genetic liability to the disease.

So, the interpretation here is actually that you're saying that there's a genetic effect

on disease liability but you're also thinking that modifiable exposures influenced disease

liability.

And the result is environmental effects and that that liability will influence disease

A. But if you then through a Mendelian randomization study in this situation the liability might

have genotypic expression even when the disease hasn't occurred.

This is certain in the case of schizophrenia where it ages before schizophrenia can occur

you see effects of the genetic liability on many traits, including incidentally participation

in studies.

And in populations where no one actually has schizophrenia you see phenotypic effects of

the liability.

So, your interpretation here actually is to the disease liability.

You're again hoping that in the study you're saying something about modifiable effects

on liabilities as well as genetic effects on liability and that they may have an effect

on the outcome that you could interfere with.

But you can't let your interpretation be to the disease as a previous case.

So that's interpretation in terms of liability.

I would say that Mendelian randomization studies should always be considered in the context

of triangulation of evidence where you aim to utilize distant study designs, all of which

may have biases and have different biases, but you would aim to utilize different methods

and bring the evidence together.

Mendelian randomization would be a good method that should be put into the stew.

But that your overall interpretation is still an evaluation, a triangulation of evidence

coming from different study designs, hopefully study design which all of course may be biased,

but where the biases will be orthogonal.

Bias in one study would not generate, the mechanisms generating a bias in one study

would not apply, a study design would not apply to your other study designs.

So, I'd just like to finish by saying that I'm sure all of you want more on Mendelian

randomization and what better than three days in sunny Bristol in July 2019 when there will

be the Fourth International Mendelian Randomization conference.

The website is www.mendelianrandomization.org.uk for those of you who are interested.

I'll just leave up a PowerPoint with some further reading if you're interested in

looking at more detail in some of the points.

That's that.

Thanks very much.

MUIN KHOURY: Okay.

Thank you, George, very much.

This is Muin Khoury and I'm from the CDC Office of Family Genomics.

I'm looking at the clock here.

We have about ten minutes for discussion and so those of you in the room and on the web,

please send your questions.

I see that we have one question already.

Just to start off the discussion and again I've just being watching the field of Mendelian

randomization grow so much over the last decade in large part due to your efforts George and

it's amazing to see that now we have conferences dedicated to Mendelian randomization where

you have 200 to 300 people at a time trying to do studies.

I do remember distinctly more than ten years ago in the early days of Mendelian randomization

where we invited George to CDC to give a talk.

He flew in one day, gave a talk and then flew back out to the UK the next day.

And it was like a whirlwind of activities.

So, this just is sort of a global question and I like the idea of triangulation that

you put at the end.

I want to push you a little bit and see if others have any specific questions, so you've

used the example of selenium and prostate cancer as potentially if we had Mendelian

randomization study we may or may not have done an expensive randomized clinical trial,

even though that observation study is around selenium and prostate cancer protective effect

were quite suggestive.

So how do we actually use MR studies to either avoid or accelerate RCDs or even do away with

them?

So, for example, in this case wouldn't have done an RCT or maybe in another case we would

have accelerated or said, oh, we need an RCT here, because MR is pointed in that direction.

Or could there be situations where an RCT is not even needed and you can jump to causality?

I mean, given all the limitations of the instrumental variable approach what would be kind of your

take on the ultimate utility of Mendelian randomization to either avoid or accelerate

the process of randomization and causal inference?

GEORGE DAVEY SMITH: Thanks.

So, I think that Mendelian randomization should help virtualize trials.

So, I think it provides some evidence when you can't do a trial on cardiovascular risk

factor.

I think even 20 something years ago someone had counted 256 cardiovascular risk factors

that have been proposed.

You can't do 256 RCTs.

Now it's vastly more.

But if you're actually trying to prioritize what you would do a randomized trial on, I

would say, for example, the negative MR studies on HDL cholesterol I think would reduce enthusiasm

for having carried out randomized trials of HDL cholesterol beyond the first one or two

perhaps.

So, I think it's the prioritization.

Certainly, I would not see Mendelian randomization ever replacing randomized control trials.

I finished the first article, the first extended exposition of Mendelian randomization 15 years

ago.

We finished it by, (unint.) and I finished it by saying that we saw Mendelian randomization

as a way of helping put up the best candidates for randomized control trials, which in the

end … but they were necessary to actually evaluate therapies before.

They were definitely necessary to evaluate therapies before they came into therapeutic.

And I gain I'd also say that a negative Mendelian randomization study on its own wouldn't

say let's not do a trial in selenium … it would just feed into the evidence, the evaluation

of whether that's your best current target, you know.

Is that where you have the best evidence, is that when you can't do the trial of all

256 risk factors, these really are the best candidates.

And so, I definitely see Mendelian randomization as never doing the very randomized controlled

trials or any randomized control trial and always feeding in to the prioritization of

which trials to do.

MUIN KHOURY: So, we have a question from the web about the select study and the continuing

with selenium and prostate cancer.

Was it possible to check for genetic variance in the select RCT participants?

That would be a nice thing if those data were available.

Do you know George if such genotyping was done?

Or could that have been done and do some group analysis?

GEORGE DAVEY SMITH: I agree very much.

I don't think it's been done and I don't know if they collected DNA, I mean, trials

now would generally, large scale trials would generally at least retain samples that people

just sort of used to throw away the cells.

I mean, I remember very well doing field work in epidemiological studies 30 years ago when

we would just discard the cells after getting the serum from the plasma.

I mean, I now know it's definitely kept.

And it's definitely extremely attractive to obtain DNA and genetic data within trials

to allow replication of what's been taken from MR studies.

I don't know of any direct head to head that's been done.

That would be a fantastic study design.

MUIN KHOURY: So, we have one discussion point around the use of genetic risk scores that

will be generated from GOIS data.

So actually, one of our seminars earlier this year was on the use of genetic risk scores

in medicine, so the process of genetic risk scores usually emanates from GOIS data and

end up with having not one genetic marker or variance but thousands or dozens of them.

If you can give us sort of in a nutshell your idea of the use and limitations of using genetic

risk scores for multiple steps rather than for one gene at a time.

I mean, what would be the problems with that?

GEORGE DAVEY SMITH: Yeah.

So, the advantages of those genetic risk scores are that they obviously have very considerably

greater risk or power than any individual single genotype.

That's the advantage you have high power.

The disadvantage is that there is a balance that you've just got one instrument and,

so you can't do any of the sensitivity analyses, except you could do the interaction sensitivity

analyses.

That's the only one really of the sensitivity analyses that you could do.

The others, or the other commonly used ones are currently random, having multiple genetic

variance.

So, you have high power.

In fact, for the straightforward what's called inverse variance weighted estimator,

which is basically the slope forcing of life through to zero in the cholesterol coronary

heart disease slide I showed, that estimator doesn't have much lower power than putting

them all together in a single polygenic score.

But of course, it takes, it's a lot more effort to do up the whole stack of sensitivity

analyses.

So, I see, in terms of, I think there's also use of polygenic scores for other things

like prediction, etc., prognosis, you know, not for cause.

So, this isn't saying that this is the only use of polygenic scores in any way.

But in terms of because I see a particular use of polygenic scores is that you have high

power, you can generate them in data sets and you can use them for hypothesis generation

if you like, for looking at things you might be the factor that is influencing some downstream

phenotype.

In fact, if you're interested in that area Tom Richardson from our group has very recently

put a paper on BAO Archive, which is a negotiable web based tool which is generated I think

about 150 polygenic scores in the UK bio bank for 150 different traits.

And then you can relate those to many hundreds of outcomes in the UK bio bank and you can

… it's web available.

And so, you can look something up.

Then it's the hard work of then following that up if you do find such a … which gives

you some hint of some causal relationship.

You need to follow it up with formal Mendelian randomization studies with all the sensitivity

analyses and you need to follow it up with triangulation of evidence from other data

sets.

But there is a sort or tool available which gives you very rapid ability to interrogate

data from UK bio bank.

MUIN KHOURY: Alright, so two more questions before we let you go.

I know it's getting late in Europe here.

So, we have two questions from the web.

One of them is relevant to whether or not we can use Mendelian randomization for microchondrial

DNA.

That's something maybe we need to scratch our heads a little bit on.

The second question was relevant to whether or not Mendelian randomization can be used

to study causal mechanisms inside the cell or body, like SNIP (ph.) like an instrumental

variable finding the causal effect of gene A expression on gene B, like A regulates B.

GEORGE DAVEY SMITH: Yeah.

Okay.

So, for the first one I have to say that I have no experience of that.

And of what the phenotype was at the microchondrial DNA's infancy, because I think the key thing

is that in my view Mendelian randomization is about making some interpretation about

a modifiable exposure.

So, the question there is what is your modifiable exposure?

And then for the second question, so definitely gene expression and methylation and these

other phenotypes are indeed in principle modifiable, except where they methylation (audio) of a

base switch.

So absolutely you can do Mendelian randomization of regulation.

It does expression influence methylation, what is methylation expression.

And there are quite a few papers doing that or attempting that.

The problem is you very often have only one essential, essentially just one instrument

or variance probably with the same causal variant.

So, you can't separate pleiotropy from causation with just one instrument.

We might start producing more instruments and allow that to be the case.

And, in fact, many of you I'm sure would have come across the polygenic, I'm sorry the monogenic

model and would have been interested in that notion.

The latest paper from the group which has been posted on bio marker, they don't actually

formalize that model in terms of peripheral genotypes as they refer, call them, they have

their downstream influence in regulating core genotypes, which is a mediation model, multivariable

Mendelian randomization which I didn't talk about.

But there's a paper by Anderson in the further reading of multivariable Mendelian randomization.

It would be in fact an ideal method for testing those sorts of associations, for looking at

regulation, of looking at regulation of one gene on other genes.

So, this is an area which is in its extreme infancy, but is certainly one where some of

the methods developed in Mendelian randomization would have relevance.

MUIN KHOURY: Okay.

So, I think we're about out of time here.

So, I would like to thank you George for a very stimulating conversation and just tell

the audience that the slides will be online as actually the whole hour will be online,

maybe in the next couple of weeks.

And with that we conclude ten very successful seminars, webinars for the whole year, 2018,

which was done in collaboration between NIH and CDC.

Three of them were done at NIH and seven of them were done at CDC.

So, if you want to check out the slides and the titles and presentation you can go to

the website and so happy holidays for all of you.

And if you have ideas for topics for 2019, we're all ears and would like to have more

discussion.

So, thank you all and we'll see you all next year.

GEORGE DAVEY SMITH: Thanks very much.

For more infomation >> What is Mendelian Randomization and How Can it be Used as a Tool for Medicine and Public Health? - Duration: 1:04:18.

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Timon & Pumbaa | Rafiki Fables: The Sky Is Calling Episode 2 - Blue Goat - Duration: 3:49.

PLEASE, LIKE, COMMENT, SHARE and SUBCRIBE my video! Thank you very much!

Oh, what are you doing, you're never gonna get that thing back up there that way all you have to do is

Of course not I said I don't want to have anything to do with that thing

Don't that's good. Because remember you two are no longer bestest best friends, right?

Right. Just checking

Did I mention that guy really creeps me out

Rafiki Sean Mickey just because old blue behind said we can't be friends doesn't mean it's true

Besides I have an idea how you can get that junk back up there and I won't have anything to do with it

Maybe your brain is even smarter than rafiki's of course it is now

listen

The first thing we have to do that is you and I have to do

Independently of each other is to get as close as we can to the big bluish-black thing

To do that simple will climb really really high to the top Oh

But I'll carry it for a while

No, I'll carry the chunk because I need the exercise it has nothing to do with helping you

Now I'm getting tired

Here, let me get me the junk for a while because I want to take it all

by myself

To the top of the mountain so I can put it back into the blueish black thing where it belongs

Gee, I sure am glad I have nothing to do with that

Well, here we are I mean you and I separately at the same time

He goes nothing. Oh

Wait, you'll just throw it off the mountain. You need to send it up there not down there

Why don't you just relax for a while take a load off it's been a long climb up the mountain

No, I don't know maybe I'll build something

Yes, I'm all done building something

gee

That's something sure looks like it would be useful in getting the chunk

Back into the big blueish black thing Mitch your wood

Maybe I should build one. Why mess with?

For more infomation >> Timon & Pumbaa | Rafiki Fables: The Sky Is Calling Episode 2 - Blue Goat - Duration: 3:49.

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NLP Gym Is Going Away.... Life Mastery - Duration: 11:13.

hey Damon Cart here from life mastery gym which used to be NLP gym as you

probably guessed even though NLP gym is going away that

does not mean that I am going away and you probably notice before tuning into

this video that there have been a lot of changes on the website and here on the

YouTube channel of the Facebook channel pretty much everywhere we're changing a

lot of things that we're doing here and I started already getting questions

what's going on why are you changing the name what's the point of all this are

you still been going to do NLP processes and techniques are you still

going to do videos about this and the answer is yes

of course I am so why the change well it's really a matter of staying

congruent and this is as you know very important in neuro linguistic programming

staying congruent means saying what you're going to do and then doing it

that means what you say matches what you do so it's really about alignment it's

about having your behavior match your values having it match what you say

you're going to do I've found in myself over the probably that especially the

last year probably the last more like two years is realizing that there's

something beyond just learning NLP and geeking out on NLP which I can totally

do and I know a lot of you can and for a long time NLP has definitely been my

passion what I'm starting to realize now though is that it's very short-sighted

if all you do is learn NLP techniques and processes and cultivate the skills

without really plugging this into your life and creating the life that you want

to live and that's been coming through I feel like my videos it's been coming

through even when I'm teaching NLP processes that I'm

I have a tendency now to sort of put them in perspective for what it is that

I'm creating in my life what it is you might want to create in your life and I

just started to realize there really needs to be a bigger vision so it's

let's think of the let's use the gym analogy because it's in LP GM and our

life mastery gym you can go into a gym and make your muscles bigger and that's

fine and I used to do that when I was in high school actually my muscles didn't

get big but I got stronger and that's that's great but I eventually left it

because it wasn't doing something more for me the health part was good but it

was like stronger in order to do what and then I came across yoga and the

feeling and the joy that I got from yoga was well how is it adding to my everyday

life in other areas of my life when I wasn't practicing yoga so if you're

going into a gym and you're becoming stronger well what is it why are you

becoming stronger in order to do what what do you want to do with that

strength and so that's where I came to with NLP is what do I want to do with my

skills with my techniques with the the processes that I that I implement and if

I'm just solving day-to-day problems as they come and not doing it with an

overall vision of how I want to live my life then I'm really missing out on the

bigger picture and I noticed this with some of my students they were doing the

same thing it was it was more about a focus on just learning NLP and just

getting good at it and what I found myself starting to

teach and also coach with my coaching clients is that it's really important to

understand the bigger picture it's really important to understand the

greater vision you want for your life and plug in everything that you're

learning about NLP into that bigger vision and what a vision really is a

vision is really a direction and if you're not clear on the direction that

you want your life to go there's a you can do a lot of NLP and

you can do it for fun but it's not going to really ultimately fulfill you it's

not going to ultimately give you what you want so I decided to take this to

the next level and as you if you've watched my videos you know I'm always

talking about values elicitation I've done a few videos on it but if you've

done any of my online trainings or if you've done coaching with me you know

that's where we always start because it's so important to know what your

values are and that basically creates the vision so I sat down and I started

asking myself what is NLP Jim all of that what's important about it what does

it do for me and what does it do for you and through that process of eliciting my

values around NLP Jim I ended up with life mastery because that's ultimately

what it's about now life mastery doesn't mean mastering everything that you do

life mastery the way that I mean it is really not about coming to some place

where you can say I've mastered everything know it life mastery is about

who you become in the pursuit of your desires and your passion so it's not

really whether or not you hit the an arbitrary bar it's not whether or not

you hit some sort of goal it's taking say the next 10 years of your life and

giving it everything you've got putting yourself out there letting go of

judging yourself letting go of thinking what others might think about you or

what how they might judge you it's like what happens when you really let go and

you just go for it you allow your abilities to come out you allow your

skills to come out you allow your potential to come out of you go for all

the things that you might be too scared to go for and again it's not about the

accumulation of things it's not about the accumulation of material wealth but

along the way you probably will do that but what happens is is that you it it

makes you different it you cultivate it evolves you you discover yourself you

get better at things you 1/4 skills so it's so important that you master your

life before you master anything else so when you think about like what it is you

want to be who you want to be and what do you want to be doing and say the next

10 years dedicate the next 10 years to master in your life what else are you

gonna master there are plenty of things out there to master and I'm not saying

you shouldn't pursue something and if you're really passionate about it and

you want to practice it every single day for eight hours a day go for it I'm not

saying you shouldn't master things that way if that's what if that's where your

potential is pulling you then go for it but what I'm also saying is don't

neglect the other areas of your life so it's one thing that the master like one

specific skill and specialize in that and it's a beautiful thing when somebody

does exactly that and you watch that it's it's amazing but a lot of times

those people often neglect other areas of their life and it's not necessary you

can you can be socially connected you can have a great relationship with a

partner you can have a great career and then you can also have this thing that

you master but more important than that is mastering your life and that's by

going for these things going for your potential taking two or three things

every single year and learning them doesn't mean you have to master them it

just means learn something new discover yourself push yourself drive yourself

raise the bar set goals do things that scare you take risk and along the way

what it creates who you become is what life mastery is about I want to help my

NLP students and money NLP clients do is not just learn NLP is create that

greater vision for your life what's really going to fulfill you what would

you be doing what would you be seeing what would be happening in your life say

10 years from now you've totally mastered your life what would that be

like and NLP should be in service to that it

shouldn't be the overall focus you have to focus on it when you're practicing it

but what's going to give fuel to your practice what's going to not just give

fuel it will be the fuel of your NLP practice is that greater overall vision

of who you want to become and what is it you want to do what is the life that you

want to live and that's the direction that this channel is going that my

business is going and so in order for me to stay congruent and precise that's why

we're now going from NLP gym to life mastery gym and like I said not a whole

lot really going to change about the content of my videos it's just that I

felt like this I needed to make this update it's already been happening I

mean this is already in my videos if you've been watching my recent videos

you know that this is kind of what I've been doing anyway so if you watch my

videos you like my videos you find them useful you find them helpful please

click subscribe to this YouTube channel if you haven't already and also click

that bell so you'll get notifications and if you like this video if you like

the direction that this channel is going please click like and leave a comment

tell me what it is that your journey is about what it is you want to use NLP to

create for your life not just learning NLP for its own sake but what what is

what is it you want to use NLP to do to better your life last but not least

happy new year I hope you have some goals lined up for yourself for the

coming year I know 2018 was one of the best years I've ever had I had goals and

expectations and I exceeded all of them and it's gonna be hard to top in 2019 so

I'm sad to see 2018 go really excited about the possibilities in 2019 so I

hope you've got a vision I hope you have a plan some goals a mission and if you

don't I can certainly help you out with so make sure you're subscribed the next

videos that are coming are going to be some of the best videos that I've ever

done take care

For more infomation >> NLP Gym Is Going Away.... Life Mastery - Duration: 11:13.

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Why This 1967 Ford Mustang Fastback is Worth More than a New Car - Duration: 17:56.

welcome to wacky Wednesday's where everyone has a chance to show off their

car mods, and here's this week's winner, what's up scotty and youtube today we're

going to be featuring my 67 fastback GT 390 four-speed car and i'm gonna walk around

it let you guys listen to it and show you the

interior and the engine and yeah so let's get started,

67 is the first year for this body style so this is the second body style of the

Mustang 65 and 66 were a lot smaller cars, so in my opinion this is the

best-looking and most sought-after is a 67 fastback Mustang, and a real quick way

to determine whether it's a 67 or eight are these quarter panel louvers right

here behind the front door so that is 67 only, 68 had that deleted right there and

was just kind of a smooth shaved, so that's one of my favorite features of

that, also this is a true GT car so in 67 you had the iconic GT stripe right here

along the rocker panel and then you had the GT emblems on the fenders right

there, so on this car I have the Magnum 500 so they aren't factory to the car

but they are factory Magnum 500 and then I got the iconic BF Goodrich

radial TAs on it so just it just gives it the old muscle

car look and they're very nice tires and I actually just put these tires on the

car right before I drove it to Myrtle Beach for Mustang week this past

September, we're gonna move on to the front of the car since this is a GT it

does have the GT fog lights in the grille right here and then also it has

the GT turn signal hood, which now the new s550 Mustang incorporated that from

67, so when you turn the turn signals on it and the indication turns

on right here so it's pretty cool to have people ride in the car that's never

seen that before and then telling them that's factory from back in 1967, also on the

outside right here you have these swing windows, so I guess it's for a lot of

smokers back then so you can ash out when it's raining, but this car has no a/c

so you open it up a cool little breeze on

your legs and kind of helps out a lot so I really enjoy that, then right here we

actually have the vented louvers which is a Fastback only and since 67s the new

body style actually has 12 instead of the typical five found on the 65 and 66

models, all right let's move on to the back of the car, here in the back since

this is a true GT we have the iconic pop off gas lid right here which is one of

my favorite features as well and it's right in the middle so it doesn't matter

what side of the pump you go to you'll always be able to get gas and

then we have the iconic Mustang on the deck lid right here, so 67 was actually

the first year to actually have the letters Mustang in the back across the

deck lid, I think they carried that all the way to 70, all right before we move on to

the interior I just wanted to show you guys the exterior paint on this, this

paint job is almost 17 years old, my dad actually restored this car and he

painted it himself and it is still looking very nice as you all can see the

reflection of the sky, and I just wanted to show you all the gaps the hood gaps

and everything are all pretty much perfect, front headlight buckets are very

nice it's hard to find an old Mustang with these kind of gaps on here and the

doors just open and close beautiful nice firm shuts, all right so this car is a

factory with deluxe interior just pretty rare for these cars, which comes standard

and deluxe is the aluminum dashboard right here brushed aluminum, door panels

as well, a lot of people that do the resto mods and stuff like that and the

Eleanor kits, they kind of just put the brushed aluminum in their car but it's

not truly a deluxe interior, this door shell is actually its own part number

being deluxe interior, it has this grille down here with the speaker hole and the

courtesy light, so a lot of people don't actually incorporate that when they try

to put deluxe interior in the car, so and then this door panel as well as

deluxe, also with the deluxe package are these seats, you have these emblems into

the seats right there and then you also have these hardback

seats with the stainless steel trim around there, extremely rare and they

go for quite a bit on eBay, so one of my favorite things of the car is the lower

console right here, you can actually when you remove your seat belt and it's not in

use, you actually have these seat belt holders right here which is pretty nice, and

then the right here in the center right above the four-speed shifter, we have

what I call a easy-bake oven, so it's pretty cold here in Indiana right now so

I open that up and you get a lot more heat out right there so you can also put

some food in there to warm it up a little bit, so I've got the aftermarket

just classic looking Mustang cassette tape right there so, and then there's a

hash tray right here, alright so let's move on to the other favorite part of

the interior we're gonna look up though, right here we got the overhead console

so pretty rare, 67 was the first year to offer this, and this car has it factory

right up here in the front we have some lights, they actually say map on them

because back in the day you didn't have an iPhone to see where you're at on

Google Maps, you actually had to press the map light and then open the big map

while you're driving or your passengers driving at night and try to figure out

where you guys were, so I thought that was pretty cool

and then on the back right here we have these rear courtesy lights, which is

standard in every fastback and then we have the fold down seat which this car is

actually not equipped with a fold down seat, that's supposed to be bolted up

there, but 67 was the first year to offer as an

option not to get the falldown seat, you can see this crease right here this is

where the actual full down seat, so it would actually fully cover this and then this

would be carpet with chrome trim and then the back would

actually be a trapdoor, where you could open it and put your skis in the back or

a longboard or whatever you wanted to that wouldn't fit in the trunk by itself

so yes I would like to have a trapdoor it's cool, but it's actually more rare

not to have it as it was an option not to have it for

the first year so I think it's pretty cool that mine doesn't have it, but I

would like to have one so, but I'm just trying to keep this car original also

here in the back on fastback only, we have these air vents right here that

you can open and close that way if your riding in the back and you want to

circulate air you have the windows up you can do so, I thought that was pretty

cool, and then I do have the aftermarket

steering wheel right here, I think I'm gonna probably

end up putting the original 67 back in, have the big horn button right here but

while we're here and I'm sitting right here let's go ahead and look over the

instrument cluster, so this car actually came factory with a clock right here, I

guess it was part of the deluxe interior group, you can get all this stuff

without having deluxe interior, but I think it was standard for deluxe we also

have the hundred and twenty mile an hour speedometer and sixty-eight actually

offered 140, so first year for a hundred and twenty right there, also we have the

6000 rpm tach right here, pretty rare to have a tack, you

could actually get the tachs even in automatics but just because it was GT

doesn't mean come with the tach so it was actually a special option and the wiring

harness is actually different if you have a tach than if he didn't have

a tach, so it's very hard to actually just add one in without replacing the

whole dash harness because it's all built in, but a 68 actually started going

to eight grand instead of six, so this is period-correct for my car and then we're

going to go ahead and go down to the floor board right here, and as you can

see my brake pedal right here it's got the emblem for the disc brakes

this car is standard equipped with the four piston Kelsey Hayes disc brakes

they were on all the Shelbys and they have quick-release pads which make it

really easy to slide the pads in and out and I guess Shelby really liked that

because it was real easy to race with that way, so this car stops good

of course the rear still have drums whether it's a GT or not, it does have a

nine-inch rear end with 3 90 gears in it, and then we have the brights right here

with the foot that's your brights, so you don't have to take your hands off the

wheel to turn the brights on or off which is pretty cool, and then this

little guy right here actually does the windshield wipers which is pretty neat

actually if you press, this as a manual pump so the harder you press it the

harder it will squirt out so they did actually option the automatic ones but I

actually like the manual ones because if you have a couple friends behind you in

the drive-through you can actually squirt them so let's test that out real quick

all right let's see if we can hit Allen with this

all right so anyway that's funny I just had to show you guys yeah you can really

make some people mad thru the drive-thru if you do that or if someone's walking

behind your car like a buddy or something you just do it and they really

don't know where it came from so that's pretty cool

also one last thing while we're done here on the floorboard, I do have this

oil pressure gauge right here this is not factory but you know it's a

must-have for any of these old cars, also it's a stainless steel so it kind

of kind of flows with the brushed aluminum interior like I have, so I

thought that was pretty cool to incorporate that in here, that's probably

been in there since the 70s, all right so this is the GT 390 and 67 was actually

the first year that the Mustang had the big block in it and this car has it, they

all came with a 390 GT four-barrel engine which is considered the S code

which is the engine code for the car, also the crown jewel I would say for the

engine bay would be my air cleaner right here, right here it took me about five

years to find it and I finally scored it and got it at the 50th anniversary

Mustang meet in Charlotte and back in 2014, this is a extremely rare it's 67

GT only and you can tell that it's a GT one by the grilles on both sides right

here and this actually does not have the EGR port right here in the front, some

states you actually had that, so these are just hard to find because a lot of

people put the big chrome ones on there and stuff so these just got tossed out

back in the day, and now they're kind of hard to find, also this chrome top was

kind of its first, they actually incorporated the gt390 top lid on the 69

and 70 boss 302, so that's one reason the tops are so hard to find in nice shape

this is original shape as well it's not an aftermarket reproduction, so they're

hard to find because a lot of people put them on the boss 302 cars so

they take them from the 67 s also being the 390 GT we have the powered by Ford

chrome valve covers and then I went ahead and got the auto lite battery top

it's just to make a newer battery look old

the original batteries are extremely expensive so it just kind of works out

and kind of helps out at some shows, and then here is the the windshield bag

right here that we were squirting Allen with, so 67 is actually the last year for

the bag and then they moved on to the plastic containers for 68, 68 actually

got a lot of plastic stuff in the Mustangs that's kind of where they were

taken over with all the plastic stuff, and because it was a lot cheaper to

produce and stuff like that, then right here we have the power disc brake

booster right here on the driver's side, we do have the export strut brace right

here for the shock towers, and then just to show you guys I'm sure some of y'all

are curious on this, this is an S code car true s code, the 390's actually had this

shroud right here, and 68 had the 428 which is the first year that Ford

offered the 428, but in 67 you could actually get a 67 Shelby with the 428 so

Shelby didn't even use a 390 but being 67 factory from Ford the 390 was the

best you could get unless you special ordered the 427 side oiler and those

cars are worth big money because few of them were produced, let's move up to the

top of the hood real quick here is the wiring harness for the turn signals I

was showing you guys earlier right there, I did install a new water pump over the

summer and you can see the engine is not pristine it's dirty I've actually put

about a hundred and twenty thousand miles on this car, outside paint and all

I've been driving this car since I was 16 years old, I actually took my driving

test in it and passed the first time, no power steering four-speed car, I parallel

parked it perfect and that lady just checked off and said man you can

drive and it's kind of funny because my twin sister actually failed two times so

she was upset and cried, but of course she wasn't driving this car I was

driving it but when my dad fixed it up I actually got to drive it out in the

country you know on some back roads and stuff when I was like 15

so I kind of knew how to drive the car before I actually took the test which

was a big advantage for me, but yeah I actually drive this car it's no trailer

Queen, like I said my dad painted it almost 17 years ago and you can see it's

still very nice, especially for all the miles I've put on it, I drove this

thing to Pennsylvania, South Carolina, here you go right here Carlisle

nationals we actually got second place there in Carlisle Pennsylvania, but yeah

I Drive it no trailer Queen but it just shows if you take care of something you

know you can make it last, I take very good care of it you know I don't do

anything crazy in it and just keep it clean you know keep it waxed, keep all

the dirt off and everything and it's kind of my time capsule, I guess that's

enough talking, let's fire this thing up for you guys

that's what I call the bubbling, you never get tired of that, it actually has

the flowmaster catback with the stock manifold up front, I grew up listening

this all day long and I can't get enough of it, it's just iconic Mustang muscle

car sound for the GT 390, so let's get in there and do a little Rev and then we'll

do a drive off so y'all can hear it alright guys that's going to wrap up the

video, I'd like to thank Scotty for featuring in my car and giving us the

opportunity to share it with you guys if you want to check out some more mustang

stuff that we do we have our own youtube channel TKO resto, it's linked in the description

below, you guys gonna keep this part let me

if you want to keep up with this car, we'll be driving this car to California this spring

for the Mustang show out there, so we're going to

film everything, it's going to be awsome and we also do

Mustang restorations, so if you guys are into that you

guys can check out the channel again Scotty, we'll see you guys soon,

well that was this week's video and to have your car mod shown on my channel

here, check this out, so if you never want to miss another one of my new car repair

videos, remember to ring that Bell!

For more infomation >> Why This 1967 Ford Mustang Fastback is Worth More than a New Car - Duration: 17:56.

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Les Jones - Why is change a good thing - Duration: 0:56.

Change is good thing because we live in a society, a world today where nothing

stands still. People, environments, technology, everything is changing and

it's up to people within the dental sector to keep up with that change,

stay ahead of that change. You've only got to look back ten, 15, 20

years and think about the things you used at that time and how different they

are to the materials or the technology you're using today. Everything is changing at

a very rapid rate and if you're not staying ahead, or at least up-to-date

with those changes then your business is starting to lag behind. So change is a

great thing. Embrace it and your business will improve.

For more infomation >> Les Jones - Why is change a good thing - Duration: 0:56.

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Why is change a good thing - Nigel Jones - Duration: 0:42.

I personally think change is a very important thing. I think, obviously you

can have change for the worse, you can have change for the better but I think if

you're proactive and you're forcing and driving a change and taking control of that,

then actually you can unlock all sorts of things. People don't like to go outside of

their comfort zones and yet my past experience, throughout the whole of my career is,

I'm constantly taking myself out of my comfort zone and I've

always found it beneficial when I've done it. So I think change can unlock

things that you didn't realize were possible

if you're prepared to face it and meet it.