Genetic diagnosis, treatment, monitoring, and surveillance
Idea: Genetic analysis has begun to identify genetic risk factors. We need to consider the social infrastructure needed to keep track of the genetic and environmental exposures with a view to useful epidemiological analysis and subsequent healthcare measures. Even in cases where the condition has a clear-cut link to a single changed gene and treatment is possible, there is complexity in sustaining that treatment.
Guidelines for annotations
Notes and annotations from 2007 course
Initial notes from PT
Common readings: Khoury 2007 (Many genes as small risk factors), Paul 1998 (Complexities of social support after PKU diagnosis)
Supplementary Reading: Bowcock 2007, Frank 2005, Taylor 2009a
recap of mini-lecture for week 13
For a few years this decade, genome-wide association studies seemd to hold promise for detecting genes related to diseases and invent dug-based treatments.
But, from a week ago,
http://www.nytimes.com/2009/11/18/business/18gene.html?_r=1&scp=1&sq=decode&st=cse , A Genetics Company Fails, Its Research Too Complex
In 2009, Khoury et al. were concerned that the promises were not over-stated. Look at the table giving their quality control proposal.
In 2005, Frank cautions that epidemiology needs as much data about environmental factors as genes, but observes that the playing field is not level. (Give credit of you ever cite this powerpoint.)
Even for (rare) diseases governed by single genes, the path from genetic diagnosis to therapy is complicated as the poster-child case of PKU shows. From Taylor, "Infrastructure and Scaffolding":
- Diane Paul's ( 1998) history of PKU screening describes, the certainty of severe retardation has been replaced by a chronic disease with a new set of problems. Screening of newborns became routine quite rapidly during the 1960s and 70s, but there remains an ongoing struggle in the USA to secure health insurance coverage for the special diet and to enlist family and peers to support PKU individuals staying on that diet through adolescence and into adulthood. For women who do not maintain the diet well and become pregnant, high levels of phenylalanine adversely affect the development of their non-PKU fetuses. This so-called maternal PKU is a public health concern that did not previously exist. In short, a more complex picture of development in a social environment is needed for anyone to make use of the knowledge that the fate of individuals with the PKU gene is not determined at birth.
Genetic analysis
This week’s readings deal with analysis of actual genes, whereas most of the previous week’s readings about heritability looked at variation in some observed trait. With the expanding role of genetic analysis comes the challenge of how to fit this into our healthcare system. Genetic risk factors associated with common diseases, individually may only have a weak risk-ratio, but combinations of these factors may, researchers hope, have a larger impact of the population.
Khoury et al try to make a case for establishing standards for “presenting and interpreting cumulative evidence on gene-disease associations.” They describe problems such as publication and selection biases, differences in collection and analysis of samples and the presence of undetected gene-environment interactions among studies of genome-wide analysis. This has lead to a high incidence of type 1 errors in GWA studies (false positives). Networks are attempting to establish consensus guidelines for reporting and publishing gene-disease associations to reduce this risk. (Do a web search to see how things have developed in the two years since.)
Bowcock describes how a consortium of 50 British groups examined genetic variance in a genome-wide association study. They examined the genetic issues for 7 common diseases including RA, CAD, bipolar disorders, diabetes, hypertension and Crohn’s disease. To identify the genetic risk factors for these common diseases, they examined 500,000 genetic markers(or SNPs-single nucleotide polymorphisms) from the genomes of 17,000 individuals. They found very little difference between controls and cases, but they did find some SNPs that can be considered genetic risk factors for a particular disease, some confirming previous studies, but others identifying unique genes that affect susceptibility to a disease.
The more advanced the genetic analysis becomes, the issue of how this information is going to be utilized for the treatment or monitoring of a person’s risk for disease and what part prevention and screening plays in the individual’s health status presents itself. Bowcock cautions that translating someone’s risk into “medical practice” should not be done without “larger patient populations, well-annotated clinical databases and sophisticated environmental assessment.”
Frank's powerpoints remind us that knowledge about environmental factors is needed as well, but because it costs more to collect and store, it tends not to be collected. This will make some epi. research questions impossible to address and shape the kinds of knowledge that can be put into biomedical practice and social policy.
Social application of knowledge about genes
The Paul article gives us an example of how a rare genetic disorder, Phenylketonuria (PKU) has been managed. Even though the incidence is between 1 in 11,000 and 1 in 15,000 births, all newborns are tested for it in the US, Canada, Australia, New Zealand, Japan and most other Western and Eastern European countries. The article chronicles the history of instituting the screening procedures for PKU. PKU was described as a “treatable genetic disease.” If left untreated, it results in severe mental retardation and behavioral abnormalities. PKU can be treated by a special diet which eliminates phenylalanine toxicity in the blood of those with PKU. There were policy issues involved in the PKU screening process that warrant examination. What were the societal factors that contributed to the federal initiative in the US in 1961? Not everyone was a proponent of the testing of every newborn for such a rare genetic disease. Problems of treatment efficacy and the question of the “cost” of the program are also addressed.
As we become more advanced in genetic analysis, many similar issues may be encountered for other conditions. One current related topic is the role of BRCA1 and BRAC2 inherited breast cancer gene abnormalities. Although they only account for about 10% of all breast cancers, there is much discussion about the Pros and Cons of seeking your genetic profile for breast CA. Issues of prophylactic breast removal surgery, discrimination by health insurers and stress and anxiety associated with knowing your genetic profile are all ones that can be related to other genetic testing.
Taylor (2009a) looks in broad brush at the overall project of application of genetic information.
Annotations on common readings
On the synthesis and interpretation of consistent but week gene-disease associations in the era of genome-wide associations studies (Khoury et.al, 2007)
The article discuses the challenges and the attempts to improve the interpretation of effects genes have on various diseases. The authors argue that while effects of some specific gene variants can be small, multiple genetic variants, when in combination, may offer better explanation. Their assumption is that numerous genetic variants when replicated have weak (with risk ratios <1.5) but constant effects and those should be distinguished from spurious effects that are result of methodological (or some other -DBJ) biases, like publication bias, data dredging, etc. For example, they looked into 25,000 publications in the CDC online database and found that 84% of those publications were based on case-control studies that analyzed effects of one or a few, but not more than five specific genetic variants (p.440). Later they also bring the interaction of genes with environmental factors as something important to account for when looking for causes of common diseases. One of the concerns that authors raise when discussing biases (especially biases from spurious associations) is that and while careful replication may mitigate some of the biases, it can also result in wasted resources. So, in conclusion they ask “are we there yet?” and their answer is “no for years to come”.
For me, this article raised somewhat different questions:
1) When it comes to genes and interpretation of genetic causation, how much do we understand and how successful can we be at analyzing if our understanding is still limited?
2) How much the (under)development in the genetic field is the result of complexity of genetic science and how much is it due to ethical concerns? What is the bigger issue- the process (replication) or the restrictions (due to public policy and public opinion)?
3) How much better understanding of gene-associated diseases may result in slowing down the disease progression or finding its cure, and how much it would make it more difficult for those who are identified as having the gene to be stigmatized, to jeopardize their employment, health insurance, etc.?
4) How much the genetic advancement is specific-disease-driven? How would the progress in genetic science differ if the focus was different? For example, understanding heart disease or cancer may get more public support and more research funding than understanding hair loss, but heart disease and cancer may have more complex causes, so the advancement may be slower (this is just an example, not a firm position that hair loss is easier to understand and treat-DBJ).
I hope that these questions, as well as some other questions people might have, will serve as discussion points in the next class (DBJ ’09)
Annotated additions by students
Khoury
This article calls for a standardized approach to genomic research. Specifically, the authors caution against ‘fishing’ for genes associated with diseases, as well as looking at genes in isolation, from one another, and from environmental expression of genes. Genetic influences are likely more complex than a one or two gene sequence and research in the field should be taking this broader view. In the case of environmental expression, the significance of the multiplicative, or cumulative effects of risk factors is highlighted. These authors note the heightened risk of bias, in findings and publication, due to the excitement surrounding genomic discoveries. They also cite the need for replication of findings, to confirm discoveries and rule out misinterpretations regarding the importance of individual genes, or sequences of genes.
Bowcock
In reading this article, I became concerned that the focus on the emerging genetic basis for diseases will again swing the pendulum from a population based focus to an individual focus regarding health care issues. The fascination in determining concrete ‘causes’ of disease, along with exciting research and science discoveries and innovations, may divert important attention and resources from more widespread and chronic diseases, to those that concern the affluent and influential. Combined with a potential profit motive, as discussed in the previous class, this has serious implications for health research.
Taylor
This article seems to be calling for society to ‘catch up’ to the rapidly evolving genetic research, in terms of how such research is conducted and how findings are interpreted and applied. As DNA sequencing and associated findings have emerged recently and rapidly, a corresponding social infrastructure is needed to engage multidisciplinary researchers and specialists in a standardized and comprehensive fashion.
Posted by Amy Helburn on December 1st 2009
