Genetics Training

Disease risk statistics

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Disease risk statistics

Chapter 16

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Section 1: Intro

Chapter 16. Simple disease risk statistics. In this chapter, I want to explain a little bit how we quantify risk and how we use it in genetics and how you can read our report in terms of disease risk. This is the simple part. This is really something that would be good for you to read so that to understand the report. There is another more advanced section where you find out how to multiply several disease risk statistics and so on. The other stuff is really for people who are interested and want to know more. This is the simple stuff about how to read the report.

Section 2: Odds Ratio

First, there is a term that you have to learn. The term is “Odds Ratio”, which mean a kind of relative risk. Let me explain what it means. As I have explained in the chapter about genetics, the human body has chromosomes and the genetic code is part of the chromosomes. Then, we have the genes, which are certain areas in this genetic code. Then, we look at specific variations. We do not look at the whole gene because it is the same for virtually all people, but we look at the small variations where we know that there is sometimes a different genetic letter for one person to the next.

Then, we know that for a person, for example for the diabetes gene, G in this position would mean a functional gene, we call this the wild type, and A would be the mutated gene, the gene that does not perform its function. This is what we call mutant. If you really look at the gene, the genetic variation, you can have two different letters in this case. So, as I have explained in how genes are inherited, this is another chapter that I would recommend you to look at, if you have not done so already, everyone has two copies of each gene. One comes from your father and one comes from your mother. There are some exceptions, but for most genes, this is correct. A genetic variation can therefore be only one gene, only the other, not at all or both genes. You get three different possibilities; both broken, both functional or one of them functional. With this example, G would be a functional gene; A would be a mutated gene. The possible outcome is G on both genes, we call it the wild type, so it is G here and G here. G on one and A on the other and A on both. So, A on both, a homozygous mutant, A/G or one of the two genes, would be what we call heterozygous. These are the three possible outcomes.

You might have recognized you could be A/G, but you could also be G/A, so it is not this gene that is broken but it is the other one. In genetics, we really do not differentiate. Having one of them broken is already heterozygous and we do not differentiate. It is not also easy to test which one of the two is the problem. So, if you look at the G/G, the wild type, as I said both genes are functional, here we come across this word “odds ratio”. The odds ratio is 1. This is a gene that is associated with a disease. However, the gene is not broken and the odds ratio is 1. This person has a 1 fold risk of developing the disease. This is the normal risk, the general population’s risk, so to speak.

Now, if one of the two is broken, and this differs from gene to gene, in this case it is called heterozygous with an odds ratio for example 2. This means that this person has 2 fold risk. This is 1 fold risk, this is 2 fold risk, a double risk of developing the disease. If it is a heart attack, this person has the normal risk of developing a heart attack and this person has twice as high risk of developing it. So, the risk is doubled because there is an odds ratio of 2. Then, if we say there are two mutations, a homozygous mutant, then you have an odds ratio of 4. So, it is 4 fold risk, a quadruple risk. So, the odds ratio is really a relative risk of how likely it is that you develop a disease. A person with two As will have 4 times higher risk of developing a disease than a person with two Gs. As I have said, it is relative. Compared to a person with optimal genes, you have 4 times higher risk. Compared to a person with optimal genes, you have 2 times higher risk. This is how odds ratio works. The higher the number, the higher the risk and 1 is normal risk.

Section 3: Examples

This is actually an extract from one of the report. This is for diabetes for example. Here are the genes that we test for. These are short names, TCF7L2 and so on. Then, a genetic variation has a specific kind of a catalogue number. The number is here. It says RS and a number. This is a unique identifier that tells you this is exactly this genetic variation. Another geneticist will be able to use this information to check up on it.

Then, there is polymorphism. This is really just some scientific jargon. It means the A letter has changed into a G through this variation. A G has changed into a C at position 174. The Pro amino acid at position 12 has changed into another. Really, a geneticist will know what this means. Anyone else does nor really need to know because it is some scientific information. A genotype is actually interesting. This is the actual laboratory result. As I said, there are two copies of each gene. We look at specific genetic variations in the TCF7L2 gene for example. This variation can be C or a T. These are the two different letters that could be there. As you can see here, this person has two Cs, one on each. This is a genetic result. This person has an A/A and the other one is A/A. Actually, he is not heterozygous, otherwise it would be C/G or T/A and son. This is a real unique genetic result that this person has.

Here is the odds ratio. The C/C genotype, the genetic result, has an odds ratio of 1. If in this gene you have a C/C, then you have the normal risk of developing the diabetes disease. So, there is no risk. If we look at this one here, for example KCNJ11, if we have T/T, both genes here have variation, the genetic defect so to speak, then the odds ratio is higher. It is 1.65. Whilst people with C/C have 1 fold risk of developing the disease, the person with a T/T has 1.65 fold risk. This means 1.65 times likelihood of developing the disease or 65 % higher risk than people with optimal genes. If you are interested, you can work with this. To be honest, it is some scientific stuff which is not of much relevance because we use this kind of information to find out the risk and then decide what sort of preventive action should be taken.

It is really for people who are interested in it but it is not necessarily important. There is an interesting one in here. This is a C/C genotype for this gene and this person has 0.91 fold risk. It is lower than 1 which means there is protection. While it might have been 1 fold risk, this person has 0.91 risk. It is 9% lower risk than a person with another gene. this can be higher or lower. There might be a risk or there might be a protection from the disease. Here you see RESPONDER. If it says RESPONDER here, it means that this gene responds to something or makes you respond to something specifically well. In this case, it is a certain treatment. A certain medication works better with some genes and less good with others. This means that this gene is a RESPONDER. This gene is well. It helps you. You will find this elsewhere in the report about what makes respond better.

Then, as I said, this protective. It is actually a lower risk than the normal risk. There is protection. These two create a risk that is why it says “risk” here. This is the genetic table. This is as technical as it gets in the report. Again, this is just a lab result. You do not need this kind of information to work with the program, but it is good if you understand it. Alright. This here is the actual science behind it.

This again is for experts that say, “I want to know about the scientific basis of this claim that you make”. This is one of the gene and you find them in the reports in this way. It will give you the name of the gene, some short explanation. It is really just for experts. Then, you see the three possibilities. As I said, it might be two Cs or two Ts or one C and one T. these are the three options that we have. Here you see “RES” for result. This person has T/T. this percentage here tells you the percentage of the general population who also have this genetic variation. So, this person has a T/T and 8 % of the population have also a T/T on this gene. This just shows how common it is. This is something that is very rare, this is something that most people have or how common it is. It is just a comparison. Against all likelihood, this person has the rarest gene combination out of the 3. You see here the genetic traits that this genetic variation causes. For example, the C/C causes no increased risk of diabetes mellitus type 2.

The drug, metformin, is effective. So, there is no real risk and in addition a certain drug works better. If you have a C/T, you have a higher risk and the odds ratio is 1.23. It means 1.23 fold risk, 23 % higher risk. The drug, metformin, is less effective than normal. So, metformin is not so effective for this person and you might want to use another drug. Here with two Ts, the risk is higher, 1.65. The drug, metformin, is also less effective. In case you are interested, this here is the science behind it. There are scientific publications on which we base all our claims and we state them.

This is a standard clean way of doing science to show what you base your claims on. If you are interested and you understand this scientific jargon, then you can read up on it. This is the kind of genetic information that you will find in the report and would allow doctors or scientists to work with the information and checked themselves if what we are saying is really true. So, the odds ratio is the likelihood of developing a disease. Having a high odds ratio is bad, having a lower odds ratio is good for your health in this case. However, you need to be careful. A high odds ratio does not always mean it is a big problem. Let us say that there is a disease that 20% of people get. Then, you have 1 fold risk of developing this disease, which means you have a 20 % risk of developing it. If you have an odds ratio of three. This would mean 3 times higher risk than the person with optimal genetics variations.

The calculations are a bit more complicated. If you are interested, look at the advanced disease risk statistics training. Simplified, an odds ratio of 1 is 20% likelihood of developing the disease. An odds ratio of 3 is 3 times that. It is 60% likelihood of developing the disease. The real odds ratio of 3 for this disease is quite severe. There is a very high chance of developing it. Then, you should take preventive measures to try and sort that. Let us look at this example.

There is a fictitious disease called Demo Syndrome. It is a very rare disease but there is just one gene variant that causes this disease. The general population has a normal risk, an odds ratio of 1. So, there is 1 fold risk of developing this rare disease. It is very low. Only 100 thousands suffer from this disease. Every person has a 0.001% lifetime risk. There is a low risk of developing the disease. The odds ratio relative to the general population is 1 as I said, because the general population has 1 times risk of developing the disease. Now, let us take a woman. She is unlucky. She has the genetic variation that causes an odds ratio of 60. It is 60 times higher risk of developing the disease compared to all other people. This sounds very severe. However, if you look at the numbers, the average has 0.001% lifetime risk, an odds ratio of 1. If you now look at the odds ratio of 60, it is kind like similar to calculating 0.001 times 60. It is 0.006 %. Even though she has an odds ratio of six, which sounds very severe and dangerous, the risk of developing the disease is still very low.

This means that this kind of genetic test could give a result of 60 fold risk, however, it would not be relevant for the person’s health. Really, having a high odds ratio is not good enough. You always need to look how common is disease. If you multiply the likelihood of the disease by 60, then is it even relevant or not. This is what we do. We look at the genetic effect on the disease risk and we filter out the right kind of the genetic variations that do make sense. However, some other companies and laboratories, usually internet genetic testing, do not filter this out. They just say this variation causes 60 fold risk and it is communicated. The person cannot sleep, even though it is completely irrelevant to health.

This is an important thing to consider and something that we do for you. Now, let us look at few different examples of where a genetic test makes sense and where it does not. For example, let us look at a disease that occurs in 5% of the population and the genetic variation increased the risk to an odds ratio of 7. So, 5% of the population get this disease. Any person’s risk is 5% of developing this disease. Now, one person has a genetic variation and 7 fold risk, 7 times higher than anybody else. The probability has increased from 5% to 30%. You might calculate 5 times 7 is not 30. This is because their calculation is a bit more complicated, but the probability of developing increases to 30% and if there are preventive measures it might make sense to do those if you have a higher risk because you might get the disease. This is a relevant kind of genetic test that you can do. Then, here is another example. The disease occurs in 1% of the population. The genetic variation increases the risk to an odds ratio of 1.1. What is going to happen here? You increase from 1% to 1.1% risk. There is really no benefit in knowing you have this genetic variation. The risk is negligible.

This kind of genetic test does not make any sense. Then, the disease occurs in approximately 1%. The genetic variation increases the risk to an odds ratio of 60. This is interesting. Even though the disease is relatively rare, the risk is quite high. It increases and again it is not really 60%, 1 times 60, but it is different. It is from 1% to 45%. Again, from a hardly a chance to develop it, it is a 50-50 chance you will get and if there is prevention, it would be a good idea to follow this quite strictly to reduce your risk again. This is a relevant kind of genetic information. The disease occurs in 0.001%. The genetic variation increases the risk to an odds ratio of 90. Again, from 0.001 to 0.06 is not relevant. The disease occurs in approximately 0.001%. It is extremely rare. So, you would already guess it is not going to be a sensible test but mutations lead to developing the disease in all cases.

100 % disease risk is caused by the genetic variation. There are some diseases where this is the case. This is of course relevant, because the likelihood of developing it is 100%. This is usually the case for rare genetic disorders that have a very strong impact on health. This is a highly relevant genetic test. There are things to consider. A laboratory that offers genetic tests does increase the risk to 0.06 and communicate it as a high-risk event should not be taken seriously. Really, make sure the science is shown, the disease is common enough and so on. As I said, this kind of selection has been done by our experts in our panels. You do not need to worry about this, but it is something to keep an eye on. Now, since we can find out the genetic risk, why do we not just say your risk of developing the disease is something percent? That would be more interesting.

Doesn’t it tell me more to find out I have 80% likelihood of developing Alzheimer’s disease? Isn’t that better than knowing my risk is 4 times higher? For this, I want to show you an example of why we do not do that usually. This person has an odds ratio of 3 for a genetic variation of developing Alzheimer’s disease. The disease probability is on average 20%. 20% of the general population develop Alzheimer’s disease. This is the kind of information that a genetic laboratory would communicate. But, why not say 20% times 3? Because there is prevention. Although when Alzheimer’s disease occurs, it is difficult or impossible to treat so far, there are some environmental factors that help you to either delay the onset or reduce the likelihood of it to develop.

Scientific studies have shown a number of these factors that have been beneficial. For example, drinking 2 to 5 cups of coffee per day reduces the risk to 36%. So, more than 60% lower risk of developing Alzheimer’s disease if you drink coffee, which is surprising. The reason is coffee contains a lot of antioxidants. It is a very strong antioxidant solution and Alzheimer’s disease is associated with oxidative stress, free radicals damaging the brain. This is why scientists think that this protective effect occurs.

However, even though the genes say you have a higher risk, if coffee consumption says you have a much lower risk, then doing regular exercise also lowers the risk. Then, by having a high risk here, but a lower and lower risk here through lifestyle changes, you can actually reduce your risk. This is a statistical approximation. Of course, these are not exact numbers but this would in the end reduce your risk, even though you started up with 3 times higher genetic risk, you are around 13%. So, really you have a high risk, you have other ways of lowering your overall risk, and this is why it is difficult to say your disease probability is a certain percentage because the aim is really to reduce this.

The same person living in an unhealthy lifestyle, smoking, drinking, no intellectual challenges, will increase his or her risk of developing the disease. Here the probability can be higher. While a laboratory can really detect 3 times genetic risk, what else the person does to his risk is up to him. It is really difficult for a laboratory to calculate “this is your probability of developing the disease” because it is modifiable and changes with your lifestyle. What a laboratory needs really to do is tell you the genetic risk and tell you in which way your lifestyle should be changed to counter act the genetic risk. This is the concept of preventive genetics.

Section 4: Summary

The genetic risk is stable and unchangeable. It is inherited and it will stay the same. Any other laboratory analyzing the same genes should get the same results if they work scientifically. Different analyses of the same genes should yield the same odds ratio, even when conducted by a different laboratory. The disease probability is affected by positive or negative environmental influences. So, they can increase more or reduce the risk.

The probability of the disease cannot be reliably measured in a laboratory because we do not know whether the person drinks alcohol or does not drink coffee when he has Alzheimer’s disease risk. The aim of preventive genetic analysis is not to predict the probability of developing the disease because that is just diagnostic, there is no use in this information, but it is to influence the risk of developing the disease by modifying lifestyle or environmental factors in such a way that the disease risk is lowered, even though there is a high genetic risk. That is the aim. So, really that is why we communicate your relative risk. It is a stable number there in your genes.

Then, preventive genetics tries to help you modify your lifestyle to prevent getting this disease. This is the end of chapter 16, the simple disease risk statistics, and for people who want to know more, only for those it is not necessary, you can also look at the next chapter about advanced disease risk statistics and you are going to find out more information on how odds ratios are combined and so on. Thank you.

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