Youtube daily is it 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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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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BEST LUXURY PURCHASES OF 2018 (TRIED & TRUE & TOTALLY WORTH IT!!) - Duration: 5:51.

hey guys it's Cassie welcome to my channel if you're new welcome back to my

channel if you're a seasoned member of the 2102

crew

today I'm going to be talking to you about the best luxury products that I

bought in 2018 these are the OGs these are the ones that have done me

good for the last year so guys if you're new here my name is Cassie I am a

self-diagnosed luxury addict and I put out videos on Wednesdays and Fridays so if

you like luxury fashion then you're probably going to like those too head

down there click the subscribe button turn on the notification bell become a

member of the 2102 crew okay guys let's start don't be angry with me okay

because I know you've heard a lot about her but she's worth every second okay

but the first one is my Dior saddlebag I am obsessed with her okay I am so glad

that I got this bag I did a full review of this bag which I will link below so I

will not bore you with all the details but basically I love her even more than

I did when I got her how she goes with everything I actually have never really

had a very like short handled bag I'm more you know like a crossbody or a top

handle I'm really not this kind of like in-between but I'm very here for it

I'm very here for it she's iconic she's an amazing shape I'm so glad I got this

blue color as well because it just matches so well with jeans and she's a

babe and I love her and she is everything there is another bag that I

got this year that I absolutely love and that I have used so much and that is the

Gucci GG supreme belt bag yes this bad boy just is the most easy thing the

majority of the time I wear her cross my chest right just you know like a little

titty pocket like a titty pocket and you just slang her on and off you go again

she looks so amazing with casual outfits and I have just been so impressed with

this bag I've had this for since the beginning of this year and she is still

in amazing condition again I did a full review of this which I will link below

if you're interested but this she is she's like G you know she's like my

OG she's she's a real one she's a real one moving on to shoes when

we were in Miami I saw these on sale for like half price and I was like good

evening yes I'm a size 39 do you have it yes okay box her up I'm having her she

just this gray is such an amazing neutral color that goes with everything

and I love the fact that in the platform you have these little these little stars

and little pearl studs there so that you know she's not just average

oh no they add a little bit of extra something to the outfit that you've got

that cute little ankle strap situation at the top there I die again matches so

many things this is just such a winner for me the next shoes I'm gonna talk

about are my Gucci ace crystal sneakers now the thing about these is is that you

wouldn't necessarily think because of all the crystals you probably don't

think like ooh I can't I can't wear this on a day-to-day basis

she's too extra she's too much she's too bougie incorrect with every single

casual look top it off with these literally just treat her like a pair of

stan smiths treat her like a pair of just you know normal low top white

trainers and she just she just kills it I've had them for a year now and not a

single crystal has fallen off I just die I'm obsessed they're me they're extra

they're everything so happy I got these another pair of trainers that I got this

year and I fought tooth and mother-effing nail for these shoes if

you want to hear the full story about that I'll leave it below you're just

like effortless Chanel chic I just I love how bright they are again I will

just wear a very plain basic outfit and hit it with these all black hit it with

these white white tee and jeans hit it with these if you want me to do a video

on how I style luxury sneakers so I'll do like a low tops and a high tops let

me know because A I would have so much fun doing that video and B you might

find it useful I love them I've been keeping her close to me I don't put her

in any dirty situations and she's cute she's

killing and she's a babe and then the last product that I am

super happy I got this year are a pair of prada sunglasses they come in this very

cute white box pop the trunk and these are okay these are like my most trendy

sunglasses because I didn't really go for the skinny skinny trendy sunglass

mood and then I saw these and I was like hold on she can get it excuse you excuse

you again just an outfit elevator I am wearing this boring-ass white sweater

but do I boring now hoe no I don't because topped it off with these glasses

and I look hella chic do we agree I agree

I feel famous I feel famous in them and that is really the end goal with

anything you buy is that whatever it is if you feel famous it was a win let me

know in the comments which of these things you liked did you like any of

these things were you like yes Cassie that is a great purchase well done girl

what were your great purchases this year let me know like this here if you liked

it subscribe if you haven't already become a member of the 2102 crew

guys have an amazing morning afternoon or evening wherever you are and I will

see you in my next video bye guys

For more infomation >> BEST LUXURY PURCHASES OF 2018 (TRIED & TRUE & TOTALLY WORTH IT!!) - Duration: 5:51.

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Man City star admits Thursday's Liverpool showdown is a game they must win - Duration: 4:31.

  Bernardo Silva admits the pressure is on Manchester City in their title crunch against Liverpool

  Champions City host table-topping Liverpool on Thursday in a mouthwatering and potentially decisive clash in the race for this season's Premier League

 Having allowed Jurgen Klopp's unbeaten side to open up a seven-point lead on them, Pep Guardiola has warned his players that dropping any more points will doom their hopes of retaining the crown

WIN £25,000 for FREE with Footie5 - click here to play  And Portuguese playmaker Silva said: "Is it must-win? A little bit, yes

We know the pressure is a little bit more on us because if we don't win it will be very difficult to go after them

 "That's what we will try to do — it's what we try to do every game. We will try to win the three points, especially with our fans and we'll try to win that game

 "We have to think about ourselves, we have to think that we have to win every game possible to try to reach them, to close the gap a little bit and that's what we'll try to do in the next game

We know we are seven points behind and if we win it will be only four - seven or four is very different - but we'll put some pressure into them

 "All games are important when you play against one of the contenders. Read More STAN COLLYMORE: Even a 5-0 Liverpool win over City won't make them my title favourites  "When it's the team that is in the first position it's even more important, because you're not only winning your points but you're taking them off their points

 "They're unbeaten until now in the Premier League and we'll try to end that."  City will know exactly how Liverpool are feeling having been in the same position last season — going into the new year with momentum and an aura of invincibility around them after an unbeaten start to their league campaign

Read More Liverpool's Andy Robertson bracing for Man City to come at them "full throttle"  That ended at Anfield in mid-January, when Liverpool became the first side to inflict a league defeat on them

 Silva said: "It's better to be that team than what we are right now. They've had a lot of clean sheets

An impressive defence. The front three, everyone knows how good they are. They work a lot

The midfielders they work a lot, they press a lot.  "We know them, they know us. Read More Raheem Sterling warns old club Liverpool before "massive" Man City showdown Football news straight to your inbox  Never want to miss the latest transfer news or match reports?  We've got newsletters sending you the latest from the football world or, more specifically, for Arsenal, Chelsea, Liverpool, Manchester United, FC Barcelona and Real Madrid

 Sign up here to receive stories straight to your inbox.  "This season, they've been doing very well in the Premier League and the Champions League

So it's two very good teams."  City will be pleased to see the back of December, after losing three of their final five league games in the month

 They ended the year with victory at Southampton on Sunday and Silva said: "After that difficult moment of losing three of the last four games in the Premier League, it's good to come back from that and get a win before that game against Liverpool and get our confidence back to where it should be

" poll loading What's your prediction for Thursday night? 5000+ VOTES SO FAR Man City win Liverpool win Honours even

For more infomation >> Man City star admits Thursday's Liverpool showdown is a game they must win - Duration: 4:31.

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Why Is It Important To Serve Your Community? - Duration: 13:51.

We know service is good. But in this video, we're going to dive a little bit

deeper into why serving in our community is important. Of course, I brought back

Devin Thorpe for this conversation. This is an awesome conversation. Let's start

at the basic level to begin with why is serving in our community so important?

-Well, it is for a variety of reasons. But at a fundamental level, one of the things

that I would point out is that we all have a place in our brain that is

activated by altruism or that motivates us to do good for others. It is

a distinctly human trait as far as we can tell. But it's a really powerful need

that we all have. To do some good. And so doing good in the community is a really

powerful way to sort of activate that part of the brain. And I realize

everybody feels that a little bit differently but virtually all of us, feel

that to some degree or another. And we can activate that part of our brains

even if it hasn't been active by engaging in service... -Okay, so I've got a

question that will flip it around then. What are some of the negative impacts

that I might experience if I'm not serving in my community? -Our lives... There

are so many different people and I'm certainly not a psychologist. You and I

know one. You could ask him about this. But my experience in the research

I've done suggests that there is really and truly a level of human satisfaction

that comes from doing good. That if we don't have that in our lives, we're

really missing out. All kinds of data suggests that people who do service and

give service are happier in life. They're happier in their jobs, it's almost

kind of magic. I don't want to dismiss for a minute,

you know, clinical depression and that sort of thing. But clearly, one of the

treatments for depression would be some service to get you out of your own head

a little bit and focused on others. So, yeah. That's an awesome point to

bring in. So, even biologically or just just physically, I will feel

differently. I'll experience life in a different way

whether I'm serving or whatnot. -And most people do. Most people are doing giving some of

their time or money to a cause every year. And so we're really talking about a

minority of people who don't do anything. So, I've got a question for

you. Maybe you can help me out because like there's actually an area where I'm

struggling where... And it's just a mental

struggle. I feel like I love to give but I am also... I also judge quite a

lot. -Mm-hmm. Well when there's a... When there's a panhandler, I'm really

judgmental. And I don't like to give to panhandlers. You know, people on

on the exit ramp on the freeway. And in my mind, I've actually made an

intentional choice instead of giving to people that are on the street corners

asking for money. But I'm going to make an intentional choice ahead of time that

I'm going to be a good tipper for the the waiter or waitress at the restaurant,

for the Uber driver. And part of me still feels guilty for making that choice.

Because it's... I want to give and I love people that are there giving of

themselves. Obviously the person at the restaurant of their Uber driver or

other other places that I can give a tip. Was just in New York there is a tour

guide that I that I went on and they're obviously they have these jobs because

they want money. They're essentially saying... Holding up the sign

saying, "Hey, I need money." And for some reason, I feel great and I love giving to

people in the form of a generous tip. But at the same time, I'm judging people on

the street corner not wanting to give them a tip and I'm judging

they're going to do with the money and choices they made in their lives. So how

can I... -Yeah. So... No, that's a really good setup. And I would point out

that it's really an important lesson to be thinking about most of the people

you're tipping. Not all. Some are quite well-off. But many are not well-off

by your standard, right? They are in a situation where they may or may not have

good health insurance, they may or may not have health insurance for their kids,

you know, who knows the situations. So yes, being a fair, generous tipper is I think

a moral good for sure. I commend you for doing that. Giving to panhandlers is very

controversial. Sadly, there are some panhandlers who are not very hard up. If

someone has a car and a clean warm place to sleep every night and their

panhandling for an income that offends me. Many of the homeless people I

see around aren't actively panhandling. They get a variety of services. Some do.

Especially those that have habits that they need to feed apart from food. So

yeah, it's very controversial. And one of the things that I try to remember and

encourage other people to remember is that they are all human beings. Whether

it is a faker, a manipulator, is panhandling and going home to a warm bed

every night. There's that. I try to remember they're human beings. And they

may not have a much better way to maintain that lifestyle. In our economy,

there are a lot of reasons people are displaced. I would like to think that

they could do better. But on the other hand, you and I know here in Utah, you

don't make $15 now are slinging burgers at McDonald's. If you can make $15 an hour

panhandling, our economy is screwed up. As much as that person is, right? Anyway,

so I try to see them all as human beings. Even those who are addicted to heroin

and there are a lot even here in Salt Lake. Of course who are struggling with

terrible demons. Of course we have some who are mentally ill. And so one way to

cope with that dilemma would be also find an organization that supports

homeless people in a way that you... That aligns with your values. So, there are all

kinds of halfway houses and programs and... So you know, you can give to a homeless

shelter. It helps people get off the street at night so they're not dying of

exposure overnight. Every year in Utah about a hundred people well in Salt

Lake. About a hundred people in Salt Lake die from homelessness every year. By and

large, that doesn't sound like a lot for a big city. But we're only talking about

a population of homeless of chronically homeless people of 500 or a

thousand people. So like, 10 or 20% of them are dying every year. It's a

horrible horrible life of tragic. So, there are all kinds of organizations

that are providing food, shelter, job training, drug treatment. All kinds of

things. And we can and should give to those organizations for sure. You know,

we benefit. We benefit from eliminating homelessness. Homelessness in our

community is a real scourge. And it's expensive. It has a negative impact on

all of us. It's uncomfortable with it as it is for you and I to see it. We have

to remember it's a thousand times worse to experience it. And there are way too

many people in our community who experience it for brief periods of time.

That is clearly a problem of our economy that is sometimes a problem of our

healthy economy, right? Rents go up, home prices go up, wages don't seem to keep up

with inflation very well in our country. It's a country

problem. And so, we're seeing more and more people experiencing homelessness.

Not in a chronic sense like the folks we see downtown that haven't bathed in 6

months, right? It's the people who get evicted from their home because

they can't keep up with rent, something happened. Job interruption,

you know, they got laid off, a health problem. You know, medical problem took

all of their money. I mean, all kinds of different things that we would frankly

say, we're no fault of their own. Puts them out on the street. Now they have no

money for a first and last month's rent and a deposit. And they're homeless. And

they're in the system. So, there are a lot of systemic things that we can be

looking at in our communities. Perhaps the biggest to alleviate at least that

form of homelessness is to look at affordable housing policies. And for

landlords to look at carefully alternatives to eviction. Because

eviction in and of itself creates that cycle. And I think landlords can do more

to avoid that some of the time. And the fewer evictions we have in our community,

it will reduce dramatically. These period people that experience

homelessness for 3 weeks or 3 months as they transition back into

housing. And we need to eliminate those gaps through this a variety of

things. -I can see those being a tough one. I'm not a landlord but I have

done a lot of filming for a real estate investing YouTube channel. And you know,

there's a lot of... There's a lot of risks that you have to mitigate in

order to be profitable on your rental. And so, you know, to bring in that idea of

if you're going to evict somebody, they're going to become homeless. But if

I don't, I'm going to go into the negative on this property.

That's a tough one. The alternative is necessarily not to collect the rent. And

I realize I am a very small sample but my parents had a rental place and the

tenant was 5 months behind. It was a disaster. It took us a year that I went

in. And I was a real jerk/ I'm sure the tenant hates me. But we kept her in that

apartment for 5 years. And of that 5 years, she probably paid the rent on

time in 12 months out of 5 years. She was a candidate for eviction for almost...

Well for 48 months of 60 months. But we kept her in there and yeah, the way I

dealt with it was to be a jerk. I would go over and sometimes yell at her. Get on

the phone and yell. Horrible but we kept her in that house for 5 years.

But there are alternatives to eviction. You know, you can in some cases do it. But

you know, there are a variety of other policies that we need to be do. We need

their federal subsidies available for some housing. But the city's probably

need to be committing resources to this as well.

They don't enough. Even in very liberal Salt Lake City, I don't think the city is

doing nearly enough to create and incentivize affordable housing.

Affordable housing can be profitable. We need regulations that make it easier

for it to be profitable. That may mean code that allows for smaller dwelling

units for more people. Trust me, a family of 4 is happier in 4 hundred

square feet than on the street. So, we need to be really thoughtful about all

of those issues and how they come together. Because if we can keep people

housed, there are all kinds of other peripheral community issues that can

also be avoided, community problems. -Well, I appreciate this discussion. One,

appreciate the discussion on you know what are the benefits of serving in the

community. And then just kind of expanding it that there are there are a

variety of ways of doing it and if there's... In my case, I brought up a way

that you know, I see a problem here but I've got a conflict of how to help there.

And you've pointed out several different ways. You know, there's ways that

we can help with housing and even just... Anyway, so I appreciate that perspective.

Hopefully this video was helpful to you. Share your comments below on the

benefits that you get from from serving others serving in the community. Now, if

you want to find out more information about Devin and the great things that

he's doing, I'll put a link to your YouTube channel and website. I'll put

that down below. So be sure to subscribe and we'll see you tomorrow.

For more infomation >> Why Is It Important To Serve Your Community? - Duration: 13:51.

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Another Year Is Dawning - Duration: 2:39.

Another year is dawning

Dear Father, let it be

In working or in waiting

Another year with Thee

Another year of leaning

Upon Thy loving breast

Another year of trusting

Of quiet, happy rest

Another year of mercies

Of faithfulness and grace

Another year of gladness

In the shining of Thy face

Another year of progress

Another year of praise

Another year of proving

Thy presence all the days

Another year of service

Of witness for Thy love

Another year of training

For holier work above

Another year is dawning

Dear Father, let it be

On earth, or else in Heaven

Another year for Thee

For more infomation >> Another Year Is Dawning - Duration: 2:39.

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Is Grammarly Subscription Worth It? Grammarly Review - Duration: 4:02.

So by now you might have seen some ads of Grammarly

popping here and there on youtube

or you are just looking for the review of the Grammarly.

Then you've just landed on the right video.

In this video we will take a look at the Grammarly

and see if it's actually worth it.

So I'm assuming you are teacher, student, employee, worker, boss.

who writes assignments, legal letters, proposals, etc.

Basically anything in English.

Then you will mostly face a problem of not knowing wether the stuff you're writing down

is grammatically correct or not.

Even myself whose native language is not English.

I do face this problem a lot.

And this is even critical if you are composing a proposal or a legal letter.

So to help us here we need a tool which can correct our grammar,

check the plagiarism and make some sense of stuff we are writing.

So there are many tools which can do this for us

but what mostly people do is just they send this letter to their grammar nazi friend

and they will correct it for them.

But let's be honest guys this is not very reliable solution.

Or Second thing what people do is just put their precious document

on to a random grammar checking website

and hope to get it right

but even though those websites also use the grammarly ghost, which is basically grammarly.

So the best way to do this which I personally use is by using grammarly.

It corrects your grammatical errors,

increases your vocabulary and also

built in plagiarism checker and many more features along with that.

Now for this review of it break it down into three things.

First is the speed, second is plagiarism and third is the availability.

So first of all let's talk about speed of grammarly.

For speed I would like to rate grammarly five star out of five stars.

I'm saying this because recently I did my final year thesis

Running out of time,

vocabulary and confused is my grammar correct and

it's not that I have the

time to check grammar mistakes.

At that time I new but grammarly and sign up for a free trial

and use the only free features.

I was also still in doubt if I completed my thesis

but after that it got plagiarised

and that was the time

I purchase the grammarly premium which $29 a month.

Yes it helped me a lot in completing my thesis with 10% plagiarism

which was because of review

and literature study

and I was just typing it on whatever was coming to my head

and grammarly corrected that for me.

So that's why I rated the grammarly a 5 out of 5 star in speed.

So the second one is plagiarism.

Yes it's really helpful.

It can check plagiarism while you're typing

and search for the online content that

has similar text in it.

Plagiarism is very important if you are doing SEO work

because Google always love original content

and it will penalise if you copy from someone else website.

So mostly in colleges what teachers use it to check the plagiarism is turnitin.

but grammarly can only check the plagiarism only online database which Google has indexed.

So I would like to rate grammarly 4 out of 5 star rating in plagiarism.

So the last one is the availability.

If you write manuscript or assignment I bet you're using Microsoft Word.

Grammarly supports all major apps and now it is available on Android and iOS devices.

So I would like to read grammarly 5 out of 5 star rating in availability.

Now finally I will rate grammarly according to the person that is using it.

For digital agencies, SEO work, writing legal letters, communication with customers

I would like to rate 5 out of 5 star rating.

Now if you are student, I would like to rate grammar only 4 out of 5 star rating

because there are many more software if provided by the college

to check the plagiarism and check the grammar.

So if you want to take a look at the grammarly by yourself

you can check out the links down below description

and start your free trial

but I highly recommend you should get the premium version,

as it will save a lot of time.

But anyways that was today's video

hope you guys enjoy this and if you did just click the like button below,

share this video with your friends and subscribe to the channel if you haven't yet

and I'll see you guys in the next one!

For more infomation >> Is Grammarly Subscription Worth It? Grammarly Review - Duration: 4:02.

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Why is communication important in business? | Express Gut Instincts - Duration: 1:18.

Hey guys! I appreciate you tuning in for this episode of The Mental Minute. Today,

I'm going to be talking about communication, and the best way that you can

get the information that's up here, coordinate it with your gut, and then

externalize that. You know, when I was having a lot of issues processing things,

I realized that I had a lot of information up here, but I just didn't

know how to express it. And the problem that I had is that anytime that I

would have some sort of communication with somebody, generally, I would always

fill in the blanks because I thought it was just an excellent opportunity for me

to get out what was up here and externalize it. However, I realized that

was actually the wrong thing to do it. So, here's a tip on how you can improve your

communication with somebody: only respond to questions being asked. Don't respond

to statements, don't respond to basically anything where you interject any sort of

opinions unless asked. The reason that you do that is if somebody

wants to know something from you, eventually, they're going to ask. The

problems that you may have is that when you attempt to fill in the blanks and

give information, it's not necessarily what the other person is thinking.

For more infomation >> Why is communication important in business? | Express Gut Instincts - Duration: 1:18.

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Keto 101 - What is KETO//OS® NAT? - Duration: 2:56.

So how does Prüvit lead the charge with innovation?

You know

You know when you look at one of things at the core of Prüvit's foundation

is, it's education

and education helps drive the innovation and the new technologies

that are being brought to market.

But I want to look at this from a different perspective,

when you see companies like Apple is innovative, right?

they bring out new innovative things.

Its one thing to be innovative, its another thing to be disruptive.

And constantly bringing together the best technologies

and finding ways to optimize them and continue to optimize them

and continue to optimize them

to make sure people are getting the best possible product.

Keto//OS® NAT is really the next iteration,

the new disruptive technology, the new innovation

that Prüvit has brought to market.

and basically the main difference is the process in which it's manufactured.

It is the first and only

naturally fermented ketone that's ever been developed.

and what this means is that there's no possibilities of

any contaminants being inside of Keto// OS® NAT

which ultimately is going to help

increase the bioavailability and absorption

of this technology. So what can people look for

when biohacking their system

with Keto//OS® NAT?

Really Keto//OS® NAT is there to provide this super fuel,

this alternative source of energy

that your body can then take up and utilize

for a variety of different functions

Some people come in and are looking at optimizing body composition,

some people come in and they really need that energy

they need that focus, they need that light switch to turn on

and ketones themselves

are really allowing your body to do that

and Prüvit is the only company

that has the right key

that your body can identify

that your cells actually take up and utilize

and are able to recognize to allow that fuel source

to be take up and maximumly utilized

at the cellular level.

So what makes Prüvit stand out from everyone in the crowd?

Well, first and foremost, I like to use the analogy of a keyhole.

If you think about a keyhole, there's only one key that

fits inside of that keyhole that opens up the door

and allows you to walk in. Prüvit is the only company that

has, when it comes to the ketone technology, that right key

for your cells that it recognizes

and opens up the door for ketones to

come in and be utilized at the cellular level

so that itself is really profound

and really innovative. But Prüvit is not

It doesn't just stop there, its about the support system,

its about the halo effect, Of bringing together synergistic

products that work together to ultimately make this

experience a full-body, human optimization

twenty-four seven, three sixty-five.

For more infomation >> Keto 101 - What is KETO//OS® NAT? - Duration: 2:56.

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Meditation is a Means of Transforming the Mind.It is Calm Seeing of The Nature ... - Duration: 2:01.

For more infomation >> Meditation is a Means of Transforming the Mind.It is Calm Seeing of The Nature ... - Duration: 2:01.

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Liverpool fan replies superbly after claim that Ederson is the 'best GK with his feet' - Duration: 3:58.

 Brazil are pretty lucky when it comes to goalkeepers right now.  The Selecao haven't always been blessed with talent between the sticks but in Alisson Becker and Ederson, they have two of the finest shot stoppers in world football

 It's genuinely difficult to separate the two number ones and Premier League fans have become more aware of the debate than ever after Alisson's summer move to Liverpool

 Ederson had made the transition in English football the preceding summer, proving an overwhelming upgrade on Claudio Bravo and finishing the season with the league title and Carabao Cup

 Aside from proving his competence from crosses and facing difficult shots, Ederson added an entirely new dynamic to Manchester City thanks to his ability with the ball at his feet

Ederson vs Alisson  It's a trait that also happens to be shared by Alisson, with both goalkeepers getting involved as their teams pass out from the back and also using long balls to kick start counterattacks

 There have been no shortage of clips showing both Alisson and Ederson providing the kind of passes you'd expect from a top Premier League midfielder

 And although Brazil believe Alisson slightly edges the debate, picking the superior goalkeeper is an unenviably difficult task

Liverpool fan defends Alisson  However, Ederson certainly gained himself some new supporters at the weekend, after showing off some of his finest skills during the win over Southampton

 That led to a video of Ederson completely deceiving Pierre-Emile Hojbjerg with some fancy footwork gathering engagement across Twitter, and it was certainly a neat moment

 Yet the caption of 'Best GK with his feet, I don't wanna hear otherwise,' didn't exactly go down well with Liverpool and supporter 'LFC Torres' was quick to reply

 In fact, he delivered three tweets in retaliation that have proven rather popular with Kopites, even if he had to compliment Kepa Arrizabalaga for one of the statistics

 It's a pretty emphatic reply - so check out the tweets below:  Pretty hard to argue with that, to be fair

 Ederson and Alisson are so closely matched on the tropes of a sweeper-keeper that the smallest of statistic differences play a huge role in the debate

 And like the Liverpool supporter points out, both have made mistakes with their feet before and individual errors shouldn't be used to sway the argument

 It's also interesting to note the impressive stats from Kepa who - despite trailing Alisson in short passes - can clearly compete with the two Brazilians when it comes to distribution

 No matter where you stand on the debate, though, there's no denying that both Alisson and Ederson are in brilliant form so far this season

 Perhaps the deciding factor should be which of them is lifting the Premier League title in May

 Who do you think is the better goalkeeper - Ederson or Alisson? Have your say in the comments section below

For more infomation >> Liverpool fan replies superbly after claim that Ederson is the 'best GK with his feet' - Duration: 3:58.

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When Keeping It Real Goes Wrong - Vernon Franklin - Chappelle's Show - Duration: 2:28.

You're watching, When "Keeping it Real"

Goes Wrong.

Vernon Franklin was an exceptional young man.

He was the valedictorian of his high school class,

won several scholarships,

and became the first person in his family to attend college.

He got a good job and worked 14-hour days, 6 days a week,

quickly becoming the youngest vice president

in the history of the Via Corp Corporation,

ending the cycle of violence and drug addiction

that had plagued his family for generations.

The officers of his company were wrapping up the usual

Thursday meeting in the South Conference Room

when Frank Murphy, the man who had mentored Vernon,

made an awkward comment.

Vernon, great job, buddy.

You the man. Give me some skin, huh?

Vernon got along with all of the people he worked with,

which in his heart of hearts made him feel like an Uncle Tom.

Though he could have ignored the simple comment

his mentor made, Vernon decided to keep it real.

Get your motherfucking hand out of my face.

You heard me, motherfucker. Get your hands outta my face.

What you think this is, man? Just shake my hand like a man.

"All right, give me some five on the backhand side

with all this crazy jive."

It's bullshit. Want a little soft shoe?

Should I juggle some watermelons for you, boss?

Fuck all that, nigger.

Hey, Vernon, buddy.

Get your motherfucking hands off me, Frank.

This ain't a game.

This isn't the Vernon I know.

Allow me to reintroduce myself. My name is Hov

You never heard that before, have you?

Rap music is dangerous. I used to beat motherfuckers up

just like you just for walking around my way, nigger.

Vernon, Vernon, buddy.

You better sit the fuck down, Frank.

Excuse me?

I said sit down, bitch. Thug life.

You think this is a game, nigger?

Wu-Tang.

Today, Vernon works at Sonny's Fill 'Er Up

on Route 80 in New Jersey.

He makes $6.45 an hour and stinks of gasoline,

even when he's not at the station.

It's as real as it can be.

Dollar? What I'm gonna get with a dollar, nigger?

I got kids, and that's real.

Vernon Franklin, once a heart- warming story of perseverance.

Wu-Tang.

Today, a sparkling example of when keeping it real

goes wrong.

For more infomation >> When Keeping It Real Goes Wrong - Vernon Franklin - Chappelle's Show - Duration: 2:28.

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[MV] Soyeon (Laboum) & Din Din - 사랑일까 (Is it love ?)(복수가 돌아왔다 OST Part 6) - Duration: 3:35.

Maybe this feeling is love

I have no idea what this feeling is

I want you I need you

For no reason, I want to see you once more

I close my eyes tightly and lay down

But I keep thinking of you

Yeah, well, there's no specific answer

I hardly understand my heart

At the end, I wake up in the middle of the night

You keep floating in my head

I'm fascinated by your laughter

I need to get to my senses, I need to get to my senses

Oh my you are mine, that's how I will call you

You are my lady

After we narrow it down a little

I pulled you over next to me

Maybe this feeling is love

I have no idea what this feeling is

I want you I need you

For no reason, I want to see you once more

love you love you love you want you want you want you

I can't stop thinking about you and miss you

love me love me love me tell me tell me tell me

Tell me you like me

If you feel the same way I do

I don't think we need more time

If I'm the only one who's worried like a fool

It would be better if you know too

When I see myself acting like a child, I guess that's how love is

When I see myself laughing and crying because of you,

I don't think we're just playing with fire

Oh my you are mine, that's how I will call you You are my lady

After we narrow it down a little

I pulled over you next to me

Maybe this feeling is love

I have no idea what this feeling is

I want you I need you

For no reason, I want to see you once more

I haven't told you yet, but I think

My heart must have reached you

I think I like you Baby I love you

Maybe this feeling is love

I have no idea what this feeling is

I want you I need you

For no reason, I want to see you once more

love you love you love you want you want you want you

I can't stop thinking about you and miss you

love me love me love me tell me tell me tell me

Tell me you like me

Translated by ClsQ

For more infomation >> [MV] Soyeon (Laboum) & Din Din - 사랑일까 (Is it love ?)(복수가 돌아왔다 OST Part 6) - Duration: 3:35.

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Why Antidepressants Kill Your Sex Drive - And What To Do About It - Duration: 4:21.

For more infomation >> Why Antidepressants Kill Your Sex Drive - And What To Do About It - Duration: 4:21.

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7'nin SIRRI NEDİR?Yıldızla Herşeyden Biraz/kendini sevmek/motivasyon - Duration: 21:20.

For more infomation >> 7'nin SIRRI NEDİR?Yıldızla Herşeyden Biraz/kendini sevmek/motivasyon - Duration: 21:20.

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Most EXPENSIVE And INSANE Pools That Cost A FORTUNE! - Duration: 10:31.

From pools in a palace, covered in gold to the largest pools in the world, here are 8

of the most expensive swimming pools in the world that cost a fortune!!

8.

Umaid Bhawan Palace Located in India, the Umaid Bhawan Palace

is more than just a place to swim.

It's actually both a resort and one of the official royal palaces for the royal family

of India.

It was constructed in 1943 after 15 years of work.

It is so huge, it provided jobs to over 3,500 people!!

It was so large, that at the time, it was considered the largest home in the world.

The pool itself is rather special, as it's actually underground and inside the residence

itself.

It's called the "Zodiac" and was designed in the style of Art Deco.

Why is it called "Zodiac"?

Well, if you go to the bottom of the pool, you'll find yourself looking at Mosaics depicting

the twelve symbols of the Zodiac.

But that's not the real "value" of the pool room, for both the walls and the ceiling are

covered in gold tiles.

Thousands of them in fact.

And should you be lucky enough, you can go there today and actually swim with members

of the Indian royal family, who still live there at times.

All told, the pool and palace (at the time of its construction), cost around $225,000

which would be around $3.2 million by today's standards.

Now, it is considered almost priceless.

7.

Gellert Bath Houses Back in the ancient times, it was actually

quite common practice for people to not bathe in their own homes, but in bath houses.

It was a place to get clean and hang out with other.

In 1912, the construction of the Gellert Bath Houses in Budapest, Hungary was complete.

Its style was meant to mix with the popular construction of the period, Art Nouveau.

This style adds to the class of the bath house, as fine marble and art cover the place, allowing

users to relax and enjoy a fine art show.

These bath houses aren't just one pool, but rather, several.

There are about 7,500 square feet to wade around in with varying temperatures and decor.

For those looking for a different kind of experience here, there are also wave pools,

kid pools, and even an authentic Roman bath.

However, its best feature is that the water isn't just "regular" water.

They're fed by hot mineral springs, which users claim have "healing properties".

The actual springs have been considered sacred for years, back to the time of the Knights

Templar.

You can test these properties for yourself, as these bath houses are open to the public

at large.

At the time they were built, the cost of the entire construction was about $425,000.

By today's standards, that would equal about $10 million!!!

And now for number 6, but first, what's your favorite pool?

Let us know in the comments below!

And be sure to subscribe if you are new here!

We have LOTS new videos coming up!! 6.

Nemo 33 Most people forget that there are actually

three levels of measurement, width, length, and height.

Another word to use for height measurement is depth, and if you want to find the deepest

man-made pool in the world, you need to go to Belgium.

Specifically, to Brussels and the Nemo 33 pool.

How deep does this pool go?

Well, how about 108 feet deep?

The pool is so deep that it requires 600,000 gallons of water to fill it all.

Now, you might be curious as to what the point of this pool is.

Well, it's many fold.

First off, the pool isn't just a basic pool to splash around in.

There are actually rooms and tunnels within the pool that you can go into.

And this also gives scuba divers a chance to practice or swim without having to worry

about the natural conditions of the ocean.

Not so ironically, many movie and TV productions use this pool to film their underwater scenes,

as it allows them more control over what is going on in the pool.

Granted, because of this, this isn't a pool that "just anyone" can go to and have fun

in.

But if book a class, and you have the right equipment, you'll have a blast.

All in all, the Nemo 33 pool took 7 years to build, and by the end of its construction,

it took $3 million dollars to make.

5.

Hearst Castle Hearst Castle in California has two pools

that are equally powerful and expensive.

The Neptune pool itself actually began construction in 1924 for the original residents of the

castle, and it took 12 years to make.

By the end of its construction, the pool reached 108 feet in length, with an average width

of 58 feet, and 95 feet at the alcove.

The depth reaches from 3.5 feet deep to 10 feet deep.

The second pool was built on the inside, and is a bit smaller than the Neptune Pool.

Here's the catch, while they aren't the biggest pools in the world, they are arguably some

of the most elegant.

They were crafted to match Roman era style pools, and thus have marble and tile designs

that in today's market would be a literal fortune to acquire, let alone make them into

pools.

This isn't even mentioning some of the artwork that lies around the pools, including statues

made by Italian craftsmen.

And the Neptune Pool has parts of its design literally lined with gold.

Pricing the pools is a bit difficult, as the cost to the owners isn't known.

However, including the pools and the property they're on together gives you a total of around

$10 million dollars.

Pretty impressive!!!

4.

Lev Leviev Residence Many of the world's most expensive pools aren't

for the public, or even for paid recreation.

Rather, they're for the elite who can afford such magnificent pools, such as the one you'll

find in Lev Leviev Residence in the United Kingdom.

Despite it being in the UK, it's actually owned by an Israeli businessman named Lev

Leviev, who personally paid for the construction of a lavish estate/private home that in total

cost $68 million dollars.

All so that he and his family could have a "nice" home.

Pretty cool, right??

I'd never want to leave!!

One of the most luxurious parts about this private residence is the pool.

Which is one of the most expensive private pools in the world.

Why?

Well, the indoor pool has gold in it.

And not just being lined with gold, it's actually comprised of gold tiles.

That's a gold to fill up a pool via tiles.

Not to mention that the residence has a personal spa and sauna.

But, when the time comes to be an entertaining host, Lev can use a special retractable cover

in order to make sure that the pool is covered, and turn it into a ballroom!!

You'll have to have connections to get invited though, so if you know anyone and can get

me in, let me know!!!

3.

San Alfonso del Mar When you think of a swimming pool, what do

you picture?

More than likely you picture a space that is full of people having fun in a menagerie

of ways, but for the most part, it's just people in the pool.

But, in Chile, at San Alfonso del Mar, they decided that it wasn't good enough.

They wanted to make a pool so big that you could do more than any other pool before it.

So, they made a swimming pool that was 20 acres in size.

Not to mention, one that was almost a mile end to end.

On average, the San Alfonso del Mar is actually 6000 times bigger than most public swimming

pools.

That's a lot of swimming space.

So much so that in 2008, it was dubbed the largest swimming pool in the world.

But you might be asking yourself, "Why did they make it that big?

Surely it can't be just for swimming?"

And you would be right, the San Alfonso del Mar was made as big as it was to service those

who would want to go sailing in their waters.

That's right, you can actually sail a ship (of decent size) in the "pool".

The construction of San Alfonso del Mar literally changed the world in regards to how pools

are viewed, and many other mega-pools have been built like it since.

In total, the pool itself cost $2 billion dollars, and it took 5 years to make.

Also, the entire pool is filled with ocean water that was actually purified via a special

process so that people could swim in it without getting sick or feel like they've bathed in

salt water.

2.

Seagaia Ocean Dome As most people know, there are really two

types of pools, regardless of the size they are.

The first is an outdoor pool.

The other is an indoor pool.

If you're looking for the largest indoor pool in the world, then you need to go to Japan

and experience the Seagaia Ocean Dome.

Ironically, the Seagaia Ocean Dome is part of a resort that has both outdoor and indoor

pools.

The pool itself, the inside one, is 1000 feet long, and 328 feet wide.

One of its most defining features though is its roof.

For the roof can both be retracted, and kept over the pool to ensure that it's warm no

matter what the weather is outside.

But that's not the only attraction, for the builders made sure that people inside could

still feel the rush of being out on the oceans.

So, they made it so people can actually surf waves in the pool at regular intervals.

And as though that wasn't enough, you can also see an artificial volcano erupt every

15 minutes.

For families, there's a smaller children's pool next to the big one, and a waterslide

area for extra fun.

The Seagaia Ocean Dome opened in 1993 after its $2 billion dollar construction.

It was closed in 2007 to start renovations and it's been kind of an on-again, off-again

project so not sure if it's going to be torn down or reopened.

Do you?

If you have any info, let us know in the comments below!!!

1.

City Of Stars When it comes to having the most expensive

pool in the world, there is only one true choice, and that's the City Of Stars pool

in Sharm el Sheikh, Egypt.

This pool was built by those who made the San Alfonso del Mar pool in Chile, and they

used their expertise to make this one truly shine like a star.

Just in terms of size, the City of Stars pool is massive, coming in at 21 acres.

To that end, this makes it the largest pool in the world, beating out San Alfonso del

Mar by one acre.

The pool itself is part of the resort that is called City Of Stars, which has 30,000

rooms that people can be in and then go and enjoy the pool to.

But of course, with all of this size, and the water it needed to be treated so that

the pool could be filled, the cost was very high.

In fact, it cost $5.5 billion dollars just to make this pool.

Thanks for watching!

Can you believe how expensive some of these pools are?

Which one would you be tempted to go and have fun in?

Let me know in the comments below.

Be sure to subscribe, and I'll see you next time!

For more infomation >> Most EXPENSIVE And INSANE Pools That Cost A FORTUNE! - Duration: 10:31.

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Kendra Wilkinson's Family Drama Is Even Weirder Than You Thought - Duration: 4:19.

Kendra Wilkinson's life is full of drama.

Just how much of those insane theatrics are staged for reality TV cameras is up for debate,

but the former Playboy pinup has had a lot of weird issues with her relatives over the

years.

Here's your cheat sheet on the blonde bombshell's family drama.

Her husband's alleged affair

Kendra Wilkinson's husband, Hank Baskett, made headlines in 2014 for allegedly cheating

on her with a model.

According to People magazine, Baskett insisted that nothing actually happened, but the damage

was already done.

"I flushed my wedding rings down the toilet.

I'm gonna pack up his stuff and I'm gonna throw it in a dumpster."

A source told the mag,

"She wanted to throw Hank out but couldn't because she… needs help with the kids."

The pair eventually reconciled, but the relationship still wasn't perfect.

Us Weekly reported that Baskett supposedly grew jealous when Wilkinson flirted with singer

Trey Songz during an episode of Kocktails with Khloe.

"I'm a free spirit, like, you know, I walk around naked…

I'm that girl next door."

An absentee father

Kendra has struggled to cope with the emotional fallout of her dad, Eric Wilkinson, being

estranged from the family after he divorced Kendra's mom, Patti, in 1994.

His second wife, Kathi, told Star in 2014,

"Eric has suffered immeasurably from being separated from his children.

Through the years, Patti would e-mail Eric and say, 'Your kids hate you.'

Then she'd tell the kids, 'Your father abandoned you.'"

Kendra and Eric have since reconciled, and she even attended his wedding in October 2015.

Did her mom sell her out?

Kendra's relationship with her mother, Patti, hasn't exactly been one for the books.

"I think we need to work on communication."

Kendra claims it stems from her mother allegedly selling her out to tabloids when she and her

husband, Hank were embroiled in marital drama.

"Do you know how much money I could make?"

Kendra vented, via People in 2015,

"I can't deal with my mom anymore…

She is the most sadistic abuser…

I did a lot of reaching out, I did a lot of offering for therapy, and… my mom just never

accepted."

In May of that year, Patti appeared with Kendra and Hank on Marriage Boot Camp, where Kendra

claimed,

"You sell us out to the tabloids…

The devil has eaten your soul!"

And that might actually be true.

"Wait.

My mom told me she's not writing the book."

"She's already written stuff that she's given me."

In June, 2017, Patti began writing a tell-all book about her daughter's marriage problems.

Kendra repeatedly confronted Patti about it, once telling her mother,

"You can have your family back or you can write this book!"

"The truth hurts!"

Patti didn't back down, reportedly buying a new BMW with her $10,000 book advance.

"I hope that that ten thousand dollars gets her what she wants in her life.

'Cause it cost her everything that I thought she wanted."

Different views on parenting

Kendra and Hank were still having marital problems in February 2018, according to People.

A source close to the model said,

"Kendra and Hank are struggling, but they've always had issues."

Though sources claim that Baskett is an awesome dad, his and Wilkinson's parenting styles

may differ greatly.

An insider told the mag,

"Hank is definitely more of the disciplinarian, but they've been trying to work together.

Kendra has always been focused on her career, but loves her kids.

It's a tough balancing act for her as with any working mom."

Is it all just for the ratings?

The couple's issues are constantly being rehashed on all of her reality shows.

And as a result, many have speculated that the real root of Wilkinson and Baskett's family

drama was simply her need for ratings and storylines for her shows.

"My trust level with you has gone to s---."

"If you have a problem with trust issues, then I could give a f--- about it."

But in a February 2018 Instagram post she claimed the drama was for real, writing:

"How do you fake marital problems?

Makes absolutely no sense."

She closed the post with…

"I hate drama…

I've been in a lot of therapy lately [and] hope all gets resolved for me, Hank, [the]

kids and even for TV."

"I blame myself for you not being able to talk to me."

The trouble with divorcing

Kendra and Hank finally decided to go through with a divorce, but they couldn't seem to

make it happen.

Kendra tweeted in October 2018:

"Signed my last divorce paper.

Brutal.

I gave it all I got.

Truly did.

I'm beyond proud of myself!!

Fought to save til the last second.

Oh well.

Life goes on.

Bye lol."

But…it wasn't "bye lol" for good.

According to People, their papers were filled out incorrectly, and a judge rejected their

settlement.

The good news: It appears the couple is on the same page regarding the particulars of

their split.

People reported that both parties requested joint custody of their kids.

Wilkinson also reportedly wants her maiden name restored, and wrote on Instagram,

"Been dating myself lately.

Getting to know myself and even falling in love."

"I just wanna be happy again.

I wanna be happy again, I wanna laugh again.

I wanna be back to being Kendra."

For more infomation >> Kendra Wilkinson's Family Drama Is Even Weirder Than You Thought - Duration: 4:19.

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BREAKING HUMA ABEDIN MAKE STUNNING ANNOUNCEMENT ABOUT HILLARY CLINTON – THIS IS IT - Duration: 12:04.

BREAKING HUMA ABEDIN MAKE STUNNING ANNOUNCEMENT ABOUT HILLARY CLINTON – THIS IS IT

the State Department has just released and I'm talking about just a couple hours ago

emails found on the laptop share by uma Abidine and her estranged husband Anthony

Weiner now yesterday on CNN Don Lemon who has a show there was visiblyMannoyed that

the Abidine Clinton email scandal just won't end when you clearly have

top-secret information on a laptop that you sir you have on a server in the

basement of your house and then you send those top-secret classified documents to people

that aren't even cleared to see them and then you for them to your husband

who by the way is in jail been a

million time it's water no no no no no no no we'll be right back we'll be right back

when in doubt toss to a break you learn that in anchor school 101 tom Fitton

is the reason why Don Lemon lost his mind he's the president of Judicial

Watch and he sued the State Department in order obtained the emails and he's the reason

2,800 emails are in to the public right now Tom I know this is always

a long process congratulations on getting it how many have you read what

have you found well I've read about a hundred and forty of the emails the State Department

servers went down and you know it's a big team effort at Judicial Watch it's extraordinary

that we have to get lawyers our lawyers to sue in court our

investigators look at the documents after two years we finally get the records now the

FBI found these records last year as an Henry pointed out we're

only getting them 16 months later and they show there was classified information on on

a weiners laptop in the least at least four or five emails of

that there could be others there but we're having to dig through the records

to find that out you know and the concern is you're not supposed to take classified

information off of classified systems and you're certainly not

supposed to take them out of the office and you're certainly not supposed to store them

on on secure systems like your husband's laptop and of course Weiner

was involved in all sorts of things that make his laptop especially a risky place to store

this type of information and you have to wonder why it

is the FBI and the Justice Department let Hillary Clinton and Yuma Aberdeen

off the hook after you embed the FBI knew there was classified information late last

year when Comey cleared Hillary Clinton yet again why it is they let her off the hook

now remember remember that FBI special agent who was sending these

pro-hillary and anti-trump text last year well he's the top counter Intel guy or at

least one of them at the FBI and would have been involved in this

decision making as well so it's all becoming it's all coming together we now know that

Comey other top officials at the FBI Loretta Lynch meeting with Bill

Clinton they obviously were protecting Hillary Clinton and targeting president Trump and

one of the ways they're protecting Hillary Clinton was refusing to

enforce the laws against the mishandling mishandling classified

information they left this classified info yep on the internet equivalent of a

public park bench so so if you want to know how somebody might be as president you might

say what was the last job they had and how did they handle it how did

they handle it using a private server how do they handle it not telling truthful about

it how do they handle it putting classified information on that denying

that it did and then having it turn up and then getting angry when it's

discovered in October before an election that she said classified her chief of staff sent

classified material back to her house this is a country secrets in

at least four cases you found four classified emails already it only to a couple of hundred

got to get through almost three thousand so it's her

actions that prompted law enforcement to have to act so you might love Comey hate Comey

he did not want to have to do this her actions forced him to find this and then

make a decision correct yes I do and I think you know Donna lemons gonna

be really angry when I say the following we need the Justice Department to criminally

investigate what went on here this time in an honest forthright way as

opposed to the Sham investigation that went on during the Obama administration that was

protecting Hillary Clinton their preferred candidate for the presidency

you know Jeff Sessions or I don't know if he's recused himself from this as well but

the Justice Department if this has not caused the Justice Department

to do a serious independent and criminal investigation you know then we're throwing all the

laws of against the mishandling of classified information you might as well throw all those

laws out right because

you can do anything you want and if you're powerful enough to get away with it that can't

be the standard and president Trump he's the president he

was elected to make sure this sort of stuff was stopped and I would suggest he asked his

attorney general someone in the Justice Department to at least

investigate what went on here right and by the way people say why does president Trump

keep talking about Hillary Clinton as an argument could be made there but if you flip it around

Hillary Clinton

never stops talking about this election and what happened leading up to it blaming everybody

except her own actions including Comey and wanting this

investigation when clearly she has some problems that have to be looked into hey you guys are

relentless tom Fitton thanks so much you're welcome all right Joel

Payne has a different view he's a Democratic strategist and former

director of african-american advertising for Hillary Clinton's presidential campaign so

are you curious at all about about what's on now what's in those emails

this is just a nothing burger Brian I can't believe you guys have spent 30 million dollars

you guys being

Judicial Watch and all these other conservative activists they've been going after Hillary

Clinton for years thirty million dollars chasing a ghost

on Hillary Clinton a sync something that doesn't exist now you've drugged her former aide into

this you've drugged her family you've put out misleading information

about her family about cousins and whatnot no I understand Joe

I could understand how you not want you don't want to bring it up and I respect that but

could you tell me what's misleading about our cousin going to jail

about erroneous emails about a jury finding them guilty

what's misleading about the about the anti-american newspaper that she used to co-edit let's go

through and name what

everyone at your cousin's aunts and uncles and whatnot have done over the last couple

of years that's that's ridiculous that's a ridiculous argument

that's the type of equivalency BEC that Aronian dismiss generalization that comes from this

erroneous about it well what's erroneous is that having any link to

Huma Abedin it has no link to her whatsoever it's her cousin I've got cousins who do things

that I don't agree with either does that mean that I'm responsible for their

the bottom line is here you're trying to distract from this president what he's

doing in terms of distracting from the Russian investigation this is a very smart ruse by

the way by conservative activists and Fox News Network to try to

you know treat this is top news story for the first 15 minutes of your show it's not

you're trying to confuse the American people you're trying to confuse

your viewers just a story I respect that you don't like our run down and I'm sure I won't

like a run down if you put together I might not like the order in

which you do it believe it or not we are covering some of the Russia investigation if you were

to now I will provide a copy for your home use a little

bit later block I'll show you okay there's a see box about 20 minutes

after but just focusing on this the number one story in America last year in late October

the number one reason that Hillary Clinton gives that she lost was the

fact that this emails who were found

on her chief of staff's husband's who's in jail for a reason we will go into that a different

time who was found on a laptop at home so State Department

things at least six of which were classified material this is a job interview a year-long

job interview she's favored to win in almost every poll

in almost every battleground state and then we see the way she acts in the

in the slip shot way in which she's handling classified information the number one reason

why she claims she lost and now for the first time those emails are exposed so this would

even

help you Joel go through it and say look I went through two thousand eight hundred pages

there's nothing here or you go through it and say wow there is a

lot here so it is newsworthy in almost anyone's newsroom I don't know what is that newsworthy

about this the sink would Hillary Clinton claims is the single

greatest reason why she lost yes it's not newsworthy for you to be chasing a private

citizen who had another private citizen working for her

for something that's been litigated by the FBI by the way your last guest

doesn't think the FBI that I think he

wants the FBI to be disassembled I think that's what he sounded he said that the the FBI in

some of the FBI is a tool of the Democratic Party is that as Brian is

that your opinion on this the FBI is infiltrated by Clinton Democrat give me a break Joe I

think for one thing I think your point out you give me a

chance to separate the rank-and-file the FBI I've had a chance to spend a

great deal of time with and there's about thirty five thousand in the country to think

that if there's anything mental thirty five thirty well

thank you and if I did meet him I would share their names with you but most of those I've

meet there's about thirty five thousand the country I'd say 99%

are doing things on a regular basis that are extraordinary not for fame not for

fortune not for a pat on the back I get it not for their pensions because they believe

in this country however if you're trying to find out how an

investigation is progressing what is behind it what is what is why certain people are

being investigated why others you have to find out who's doing the investigating

and upon further review we're finding some some disturbing things

that are being unmasked so isMark Muller Jim called me and Bob Muller who were george w

bush's FBI team yes

they they were coordinating with the clinton campaign to defeat Donald Trump do you like

what James Comey did with Hillary Clinton's emails of course not I

disagree with it but I normal I disagree with something and II wear cave did if I disagree

with something Peter struck did if I disagree with something that Bruce

or working with justice did am I being might being critical of an entire Bureau am i integrated

the tire Justice Department or am I saying I don't

like these actions they seem to have a political motivation and if I

want to find out where an investigations going I have to find out who's doing it to me those

a logical questions Joel that you would be asking to well I'll do respect

Moran I'm I'm more concerned

with our commander in chief and how he feels about this he spent the last week before Christmas

going into Christmas holiday tearing apart the career of Andy

McCabe who by the way has spent the last 20 years fighting terrorists doing things that

your network before is the care about so yeah that's what your

president believes in so I'm more worried about what he thinks and not what you think

seven and a half hours behind closed doors so disturbing was it the guys rush into retirement

For more infomation >> BREAKING HUMA ABEDIN MAKE STUNNING ANNOUNCEMENT ABOUT HILLARY CLINTON – THIS IS IT - Duration: 12:04.

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Stunning THE HILLSIDE it was one of the greatest ideas I've seen - Duration: 2:56.

Stunning THE HILLSIDE it was one of the greatest ideas I've seen

For more infomation >> Stunning THE HILLSIDE it was one of the greatest ideas I've seen - Duration: 2:56.

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News24 - Ander Herrera deserves respect for his remarks about Mourinho and Solskjaer on MotD - Duration: 3:30.

 The shadow of Jose Mourinho is not so much looming large but quickly dissipating with every electrifying Manchester United performance

   Ole Gunnar Solskjaer continued his perfect start to life as interim manager with a 4-1 win over Bournemouth on Sunday afternoon

   The Red Devils had Paul Pogba to thank for another inspired display as the Frenchman not only scored twice and recorded an assist, he put together more passes than any other player on the pitch

   This is becoming something of a theme and indeed, afterwards, at the first opportunity, the 25-year-old summed up his change in form with a relatively obvious dig at Jose Mourinho

   "We want to attack. The manager wants to attack," he told Sky Sports.   Pogba is far from the only player to be rejuvenated under the new regime and Marcus Rashford was also at his scintillating best at Old Trafford

   Once Rashford had set up Pogba's opener, it was over to Ander Herrera to supply the second with a superb cross into the box

   Yet his post-match interview took a rather different tone to that of many of his team-mates' recent comments

   "We have won the last three games but I do not like to make comparisons," he told the BBC's Match of the Day, quoted via Goal

 "I am very thankful to Jose for what he did to the club.  "Now we are in a different moment and we have a new manager and that is it

We are in a good moment and everyone is playing very well."Herrera refused to throw Mourinho under the bus, regardless of everything that has happened this season

   In truth, United's style of football since the Special One's departure has spoken volumes

  United are almost unrecognisable   Solskjaer has simply allowed a hugely talented attack to play with greater freedom and perhaps unsurprisingly, it's paying off

   "Our attacking players are enjoying it and they are making it easier for the rest of the players," Herrera added

   "Our manager told us on the first day, the best way to win a game when you are in the lead is to keep attacking and this what the club has always been about

 "When you win and score lots of goals you want to play as soon as possible and I hope we perform on Wednesday against Newcastle as we have today

"We are still sixth but we should not be because of the quality we have."   What do you make of Herrera's interview? Have your say in the comments

 

For more infomation >> News24 - Ander Herrera deserves respect for his remarks about Mourinho and Solskjaer on MotD - Duration: 3:30.

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The beauty is so beautiful, it is wrapped up by the devil, every night! - Duration: 3:05.

Thanks you for watching !!