Question and answer of stroke heredity report

Question and answer of stroke heredity report

1. Ardell Wirokesuma (AWA) Q&A for Genetica reporting

2. Result section: Potential Difficulties in understanding values, terms & parameters 1. Does scoring of 6.2 is considered high/medium? Is there any risk grouping & difference of recommendation for each group? 2. What is the meaning of 1.87x risk of stroke? What is it compared to? This is unclear and raises question to the reader 4. What does the report mean by a ‘high’ effect? 3. Overall report uses a lot of technical terms & Terminology where laymen/ general practitioner hard to understand: example, patient will not be able to understand ‘pathogenic’ or distinguish between pathogenic and harmful

3. Answer Does scoring of 6.2 considered high/medium? Is there any risk grouping & difference of recommendation for each group? On a scale of 10, Genetica will consider dividing the level of hereditary health risk into 4 scales: less than 5 is low risk, around 5 - 6 is medium, around 6 - 7.5 is high, and above 7.5 is extremely high. The recommendation and call for action will depend on such polygenic risk scores and monogenic variants carrying by an individual. For example, scoring 6.2 is considered high, the suggested actions will be depended on the number and recommendations of gene variants decoded. What is the meaning of 1.87x risk of stroke? What is it compared to? With the 12 harmful variants (shown in the sample report) that might cause a genetic tendency for stroke risk factors, such as an inherited predisposition for hypertension or diabetes. Generally, the risk of having a stroke is 1.87 times more than others of the same age group and physical condition. The higher it gets, the more likely or sooner it is for the person to have a stroke sometime in his or her lifetime.

4. Answer 3 . Overall report uses a lot of technical terms & Terminology where laymen/ general practitioner hard to understand: example, patient will not be able to understand ‘pathogenic’ or distinguish between pathogenic and harmful? The end-users will get all those information to explain the meaning of pathogenic, harmful variants during the consultation section or they can see on the video (how to read your genetic report) posted via Genetica app or website. To make it clear: Protective genetic variants associated with decreased risk of disease. Pathogenic variant: A genetic alteration that increases an individual's susceptibility or predisposition to a certain disease or disorder. When such a variant (or mutation) is inherited, the development of symptoms is more likely, but not certain. Harmful genetic variants associated with increased risk of disease.

5. Answer 4. What does the report mean by a ‘high’ effect? In our report, there are three levels of effect for each variant: High, Medium, and Low. These levels are categorized based on the corresponding scientific evidence about how each genotype could affect the phenotypic expression. Therefore, a high effect means that this variant is associated with a higher risk of a genetic disorder. For example, the GG genotype (location: 22124478) of the CDKN2A gene is associated with our cell aging process with a HIGH EFFECT. This means it is highly likely to cause a brain aneurysm, as well as ischemic stroke.

6. Result section: Potential Difficulties in understanding values, terms & parameters 5. In case contradicting results appear like for example 1 is protective 1 is harmful how will Genetica communicate this to the patients?

7. Answer 5. In case contradicting results appear like for example 1 is protective 1 is harmful how will Genetica communicate this to the patients? It is not uncommon to find genes that are listed as both harmful and protective. At Genetica, our gene panel not only includes many genes but several variants from the same gene as well. Even though they are on the same genes, it's possible for variants from different locations to have different phenotypic effects. Their overall effect on the patient's risk would be determined by our polygenic risk score, which has already accounted for the effects of many risk-associated variants on the phenotype of interest. To make it simple for patients to understand, their Risk score and risk estimate results are the final message that we should focus on, instead of the individual result of each variant or gene.

8. Interpretation: Concern of May cause informational hazards & is not B2C friendly 1. Language used – eg. ‘you’ll have a heart attack earlier’ can frighten patients and act as info hazards. How is the current market response on the wording content? Are there any chance that the such wording can be soften? 1 2 3 2. Frequent medical jargon used and can be hard to understand by patient, whereas the result is accessible directly through mobile apps. Will all these be addressed during genetic counseling & Does Genetica provide in depth interpretation guideline for prescribing doctors? For sure patient will continue follow up with prescribing doctors, so alignment between Counselor & doctor are mandatory 3 3. Some recommendations are purely lifestyle changes. Are there any regulatory/practice barrier preventing Genetica to provide clear medical follow up journey? Ex: Start inflammatory markers MCU from age 30-40, MRI above 35 with symptoms and so on. Because it will be much better if clear screening guideline is provided

9. Answer We currently have not yet received any feedback from our end-users and healthcare partners about such wording. However, we are highly appreciative of your feedback and will continue to improve our products and services. We do conduct the regular training sessions to our healthcare partners (doctors, healthcare professionals) to understand the report so that they can consult to end-user. For Genetica, during the consultation session, we do explain clearly to make sure our end users understand. We do not give any medical advices.

10. Overall report: Concern on Text heavy structure 1 6. Are the protective variants also explained? Just to give assurance to patients so not only harmful/ pathogenic variants are highlighted (lowering psychological burden) 4. Hard to distinguish between gene explanation, clinical implication & treatment recommendations all are compiled into 1 . Is it possible to separate into sections underlining what information is given? Even better if recommendation is separated 5. Some genes are labelled and some are not (ie. CDKN2A is mentioned below and this gene is not named). Does Genetica only highlight genes with high impact/association? 7. Is there any chance the report could be less text heavy/added with graphs-picture so it can be more B2C friendly

11. We do appreciate your comments and we will note for our next product improvement. For the question 5: Some genes are labeled and some are not (ie. CDKN2A is mentioned below and this gene is not named in the interpretation). Does Genetica only highlight genes with high impact/association? Are the protective variants also explained besides harmful variants and pathogenic variants? There will be variants that are more impactful than others (e.g., variants that cause disease or increase risk) so AI will select a few specific variants that have an important impact on individual outcomes. That also explains why two people have the same polygenic risk score, but each person will be very different due to the specific variants they have. Besides harmful variants and pathogenic variants, Genetica will also show and explain the protective variants. For instance, there are protective and harmful variants in the sample reports sent. Ex: Fortunately, we did not detect any harmful mutation in your PAX4 (diabetes-linked) gene that would raise your risk of type 2 diabetes, a disorder that otherwise increases a person’s risk of having a stroke. - The PAX4 gene affects the way the cells of your pancreas develop over time. The pancreas is an organ that produces insulin. Insulin is a hormone that lowers your blood sugar. High blood sugar is an important sign of a disorder known as diabetes, a condition that is a well-known risk factor for stroke. Our analysis shows that you don’t have any harmful mutation in the PAX gene that would otherwise raise your risk of type 2 diabetes. - That being said, lifestyle factors can lead to diabetes and overpower your good genes, thereby raising your risk of stroke in that manner. For example, if you’re overweight, then you should note that the American Diabetes Association recommends that overweight individuals reduce their weight by 7% in order to lower their risk of diabetes and its consequences, such as stroke.

12. THANK YOU