Dr. Hakon Hakonarson: My research is focused on high-throughput genotyping of large-scale populations of all ethnic groups, including European ancestry, African American, Hispanics.
So, the diseases that we focus on are essentially all pediatric disorders. We have recruited approximately 60,000 children at the Children's Hospital of Philadelphia.
And we focus on both common and rare disorders, neurodevelopmental disorders, such as ADHD and autism, schizophrenia, metabolic disorders, such as diabetes and obesity, and inflammatory disorders, such as diabetes and inflammatory bowel disease] and asthma. Those are perhaps the major ones, as well as cancer.
The Axiom Genotyping Solution offers a high-throughput sort of cost-effective solution for genotyping. So, today, with the cohort studies that we are doing, this is all about power. So, the more samples you can genotype, the more power you have and abilities to uncover causative, important genetic variants.
Most genotyping arrays that we have available on the market today, they offer solution for European ancestry populations, and that's sort of where most of the discovery has been done today.
And then other populations, which are sort of growing in terms of recruitment, they have more or less been used to sort of replicate findings from the European population.
But, it is extremely important to have sort of a cohort-specific or ethnic-specific arrays. We haven't really tapped into any of the discovery in these other populations as a primary cohort.
So, with the Axiom platform you can customize your way and study both common and rare variants, which is extremely important.
Because of the differences sort of in the genomic structure of different ethnic groups, it's extremely important to be able to design arrays that sort of capture the structure differences, and the Axiom platform is actually very well suited to do so.
Rare variants are very important because we have with our discoveries today more or less utilized the tacking approach, where we are not really focusing on causative variants in our research. And we see it more and more, the more we're genotyping, the more we sequence that there are very often rare genetic variants that are sort of behind the common signals.
So, perhaps most, at least many of the common complex disorders, I think we will end up seeing that there are indeed rare heterogeneous variants behind them. And in order to find them we have to be able to study them. And sequencing and sort of taking those variants forward on a genotyping platform make that very, very straight forward to do.
Most of the rare variants that they have today, they have been uncovered from relatively small sample sizes. And the bigger the sample sizes and the better the validation, the more effective these variants are going to be in your genotyping, both as a discovery sort of, you know, approach as well as tacking other heterogeneous rare variants.
Validation of rare variants is really important in terms of sort of ensuring that the causative variants that underlie the diseases that we are studying and trying to unfold that they are indeed truly causative because there's so much expense that you are going to have to apply into the translational research downstream.
So, if you don't have you're variants then validated, you may quickly go down a wrong path and spend a lot of money. So, validation is really, very critically important.
Axiom solution provides an opportunity to take a large number of variants that we generate from our sequencing studies, and we don't necessarily care whether we have some errors in those or not because we will put them on the peg [sp] and then genotype the individuals. And if there was a false discovery from the sequencing, it's going to sort itself out when you genotype.
So, it's a perfect set up for validation of the content that you carry forward from sequencing.
And you will be able to sort of go into the more genic [sp], more nonsynonymous, more regulatory, more conserved variants and take that content and put it on the Axiom platform. And then whatever is truly a real variant, it's going to genotype on the platform. You've already validated that.
Both the ease of design and the cost effectiveness with the genotyping on the platform have been very advantageous for our research.
We have used the Axiom solution now for a little over a year with very good results. And we have accurate genotypes from it that we've validated.
We have imputed the data, used it in meta-analysis that other platforms across different companies. And we have not had any difficulties with adapting the Axiom platform with any of the other platforms that we have.
So, the Axiom platform has been cost effective in terms of staff because we have been able to shift several people into other projects and programs because of the 96.
While sort of multiplexing, you need significantly fewer technical staff to generate data. That has been very, very advantageous for us.
I say performance has been very, very good. And we have had excellent call rates from the plates that we have genotyped on the Axiom. So, we have done that in sort of, you know, from different axis and they've been consistent. So, to me, the quality of data looks very good.
We have been imputing all of our genotype data. And it's sort of essentially near completion. So, imputation of the Affymetrix 6.0, the Axiom data, and the Illumina data that we have has been essentially seamless.
We've utilized the Hapmap 3 dataset, the 1000 Genome Project, and other available data. So, we've been able to impute up to about 9 to 10 million SNPs. And so, this has been very integratable, if you will, across all the platforms and no problems that we have had with those.
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