Lecture IV: Genomic Medicine: Communicating with the Patient

Lecture IV: Genomic Medicine: Communicating with the Patient
Julianne O’Daniel, MS, CGC Joan Scott, MS, CGC Elizabeth Varga, MS, CGC VO Speights, DO Erynn Gordon, MS, CGC March 2012 TRiG Curriculum: Lecture 4

What will be the pathology report of the future?
Pathologists use reports to convey data (breast biopsy report on left (AP) and BRCA report on right (CP)). How will pathology report look in the genomic era? To create the best possible reports, we need to understand more about patient-doctor and doctor-doctor communication and the issues that can arise. March 2012 TRiG Curriculum: Lecture 4

Why Pathologists? We have access, we know testing
Personalized Risk Prediction, Medication Dosing, Diagnosis/ Prognosis Pathologists If it involves testing, it should involve pathologists. As with all testing, we will need to collaborate with other medical professionals. In particular for genomic medicine, we will need to work with genetic counselors and medical geneticists. Physician sends sample to Pathology (blood/tissue) Access to patient’s genome Genetic Counselors Medical Geneticists March 2012 TRiG Curriculum: Lecture 4

Workflow must include communication
A group from Michigan has diagrammed their pilot pathology workflow for genomic testing of a tumor (right part of slide). Appropriately, they also included the left part of the slide and the importance of genetic counselors in areas such as discussing informed consent with patients and helping them understand results. This lecture will mainly cover constitutional/germline analysis. Although the genetic counseling needs will vary significantly dependent on whether the testing is restricted to the tumor or involves germline/constitutional genome analysis, similar core principles apply. Roychowdhury S, et al. Sci Transl Med. 2011; 3: 111ra121 March 2012 TRiG Curriculum: Lecture 4

Multidisciplinary Teams Needed
Modern medical technology and practice requires a multidisciplinary approach to medical practice. Greater interaction needed between Pathologists, Genetic Counselors and Medical Geneticists A key point is that the genomic testing necessitates an even greater need for a multidisciplinary approach particularly in regard to translating the sequence data into an actionable clinical interpretation for the ordering physician and their patient. (The image is from the Michigan group.) Roychowdhury S, et al. Sci Transl Med. 2011; 3: 111ra121 March 2012 TRiG Curriculum: Lecture 4

What we will cover today:
Geneticist training and professional roles Current and future of reporting and communicating genetic test results Case 1 Single gene tests Direct-to-consumer (DTC) gene chip testing Case 2 Whole genome sequencing This lecture will first describe the professional roles of medical geneticists and genetic counselors. We will then use two case examples to review approaches to counseling and communicating results for clinical care. One example will involve “current” single gene testing and direct to consumer testing and the second will look at “future” whole genome sequencing. March 2012 TRiG Curriculum: Lecture 4

TRiG Curriculum: Lecture 4
The approach Ethical and Legal Issues Pre-test Counseling Informed Consent Testing The approach taken by medical geneticists and genetic counselors consists of pre-test counseling, facilitated patient decision-making (including informed consent whether or not an official document is required), testing and post-test counseling with additional follow-up as necessary. These are all done in the context of ethical and legal issues and will typically take place over several visits. Post-test Counseling March 2012 TRiG Curriculum: Lecture 4

Medical Geneticists MD or DO Separate residency training or in combination with other medical specialty MD, DO or PhD Biochemical Genetics Molecular Genetics Cytogenetics Medical geneticists are MD or PhD trained, credentialed by the American Board of Medical Genetics. Core competencies in medical genetics can be found at More information and the location of a medical geneticist, can be found at the American College of Medical Genetics website at March 2012 TRiG Curriculum: Lecture 4

Genetic Counselors “Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease.” Masters-prepared Medical genetics Risk assessment Communication Psychosocial assessment Board certification Licensed in a growing number of states Genetic counselors are masters-prepared health professional, credentialed by the American Board of Genetic Counselors ( and trained in medical genetics, the psychosocial implications of genetic disease, and counseling. Some states license genetic counselors. March 2012 TRiG Curriculum: Lecture 4

Genetic Counselors Many work settings: Scope of practice statement: To provide expertise in clinical genetics To counsel and communicate with patients on matters of clinical genetics; To provide genetic counseling services in accordance with professional ethics and values.” Clinical expertise spans: Prenatal, pediatric, cancer, adult-onset conditions Genetic counselors work in a variety of settings. Although the majority work as clinicians, a number do clinical research, work in industry including genetic testing laboratories, or work in advocacy and policy settings. Clinically, genetics counselors are trained to address the implications of genetic and genomic conditions throughout the lifetime. Some work in specialty areas, for example, pediatric genetics, prenatal settings, cancer clinics, others work in more generalized settings. More information and the location of a genetic counselor can be found at the National Society of Genetic Counselors website at March 2012 TRiG Curriculum: Lecture 4

Geneticists as a Resource
Bridge gap between referring physicians, pathologists, and patients Develop educational material Consult about ethical issues Develop provider and patient-friendly reports A genetics professional can bridge the gap between the primary healthcare provider, the pathologist, and the patient with respect to: (a)Selecting the right test for the clinical scenario; (b)Answering questions for providers and patients; (c)Communicating and interpreting results In addition, genetics professionals often have expertise in: (a)Developing educational material for patients regarding specific genetic tests; (b)Thinking through ethical issues related to genetic testing; (c)Developing patient-friendly reports A genetics professional can be a resource to the pathologist in the genomic era by: (a)Assessing new genomic testing to determine those that are ready for patient care; (b)Test interpretation including the impact of the result(s) on the patient and his/her family.(c)Developing reports These skill sets make genetic professionals and specifically genetic counselors valuable assets in laboratory settings that conduct genetic testing. As of 2010, approximately 9% of genetic counselors worked in a laboratory setting (2010 NSGC Professional Status Survey results, website on slide). March 2012 TRiG Curriculum: Lecture 4

Geneticist training and professional roles Current and future of reporting and communicating genetic test results Case 1 Single gene tests Direct-to-consumer (DTC) gene chip testing Case 2 Whole genome sequencing We have described the professional roles of medical geneticists and genetic counselors. We will now move into the first case regarding “current” single gene testing and direct to consumer testing. March 2012 TRiG Curriculum: Lecture 4

Case 1 – Single Gene Testing
A 38 year old woman has a strong family history of breast cancer. Affected family members not available for testing She is referred for genetic counseling Breast ca 42 Breast ca 36 d.52 ovarian ca Breast ca 45 A 38 year old woman has the family history above and she is referred for genetic counseling. March 2012 TRiG Curriculum: Lecture 4

Guidelines exist for BRCA testing
The USPSTF recommends that women whose family history is associated with an increased risk for deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing. Rating: B Recommendation. There are recommendations for BRCA testing from the United States Preventive Services Task Force (USPTF). This group of the Agency for Healthcare Research and Quality (AHRQ) uses panels of experts to make evidence based recommendations. The recommendations are graded. A “B” recommendation is “the USPSTF recommends that clinicians provide [the service] to eligible patients. The USPSTF found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms.” March 2012 TRiG Curriculum: Lecture 4

Genetic Counseling for Breast Cancer
~ 1 in 8 US women will develop breast cancer Not uncommon to have >1 sporadic case in a family Only 1 in 300 to 400 have a known mutation Several steps in the process of genetic counseling Ethical and Legal Issues Pre-test Counseling Informed Consent Testing Due to it’s population prevalence and attention in the media, breast cancer is a frequent concern of adult women. Although ~12% will develop breast cancer only about 1 in have a known cancer predisposing gene mutation like BRCA 1/2. We will describe the process of genetic counseling (diagram on right) and decision for BRCA testing for the patient described in the previous slide. Post-test counseling March 2012 TRiG Curriculum: Lecture 4

Pre-test counseling is crucial
Gathering information Medical, Family and Social histories Risk assessment includes: Family Hx/Family member testing Medical Hx Risk scoring programs (BRCAPRO, Gail) Pre-test counseling is crucial and serves as an opportunity for risk assessment. Currently: (a)A woman’s lifetime risk is calculated using risk models and family history information, but in addition, if her family is suggestive, her risk might be refined further by genetic testing looking for alterations in individual genes that confer a high risk of breast cancer such as BRCA. (b)If she has breast cancer, in addition to considering tumor pathology, prognosis and management decisions may take into account tumor profiling information as well as pharmacogenomic information such as efficacy of Tamoxifen. On the right is what the currently available BRCAPRO program takes into account in determining risk for a BRCA mutation to assist on deciding on genetic testing. It involves details of family history. In the future: (a)A woman’s lifetime risk may be refined further based on whole genome sequencing which could identify both single-gene variants such as in BRCA 1/2 as well as variants that are statistically associated with increased risk, variants that modify risk, and pharmacogenomic information that help predict drug response. (b)The information would be assessed before it is needed and available as part of her electronic medical record to help guide risk prevention strategies as well as management should breast cancer occur. If the cancer does occur, her germline sequence information would also be useful in analysis of her tumor sequence to identify driver mutations and therapy targets. Parmigiani G, et al. Ann Intern Med. 2007; 147: 441 March 2012 TRiG Curriculum: Lecture 4

BRCAPRO Analysis This slide shows images from the breast cancer risk calculator from the University of Texas Southwestern Medical Center. (Entering data (pedigree) on the left and output (showing risk based on different models) on the right). March 2012 TRiG Curriculum: Lecture 4

Pre-test counseling is crucial
Presenting information Suspected differential and/or testing strategy Testing process, options Facilitate decision-making Patient/family concerns and expectations about genetics and testing Pre-test counseling is an opportunity to present information and help the patient think through consequences. Many patients do not consider the likelihood of a positive result, especially in cases of population screening (CF testing, Ashkenazi Jewish genetic testing for reproductive purposes). Encouraging patients to think through these issues PRIOR to testing is empowering and prevents patients from being blindsided by a positive result. In some cases, thinking through what they would do (or not do) with the information actually determines whether or not they proceed with testing. For example, if someone would not use carrier screening results to make a decision about an invasive prenatal procedure because they know they would not change anything about the pregnancy and do not want the information for planning purposes, it may cause more anxiety to have the test than to not have the test. March 2012 TRiG Curriculum: Lecture 4

Implications of Results: Context Matters
The informational and counseling needs depend on context and indications for testing Examples: Establish or confirm a diagnosis (Gaucher Disease) Reproductive decision-making, carrier testing, fetal testing (cystic fibrosis) Predict risk for future disease (BRCA, Huntington’s Disease) Aid management decisions (e.g., tumor sequencing) Ethical issues vary by context The context matters in counseling. Regardless of whether a formal informed consent is required, genetic counseling seeks to ensure that patients and families understand the potential results they could learn and what those results may mean. Examples: In diagnostic testing, will a positive result change management? (a) With genetic testing for Gaucher disease, confirmation of this diagnosis may lead to treatment with the enzyme replacement therapy. (b) With genetic testing for cystic fibrosis, results may be used to inform future reproductive decisions for the asymptomatic patient who is either planning a pregnancy or currently pregnant. In such reproductive prenatal genetic testing, what will they do if a fetus is found to be affected? (c) In predictive testing, there may be options for reducing risk or early detection with enhanced surveillance in BRCA mutation carriers. (d) Predictive testing may also be for the purpose of life planning as is often the case in Huntington’s disease. Do they really want to know their risk if the options for risk management are limited or do not exist? (e) Predictive testing may also be used to aid management such as in pharmacogenomic testing or tumor sequencing. There may also be unique ethical issues based on the testing/patient context. These issues and the potential implications of testing should be discussed during pre-test counseling. March 2012 TRiG Curriculum: Lecture 4

Ethics: Use of Genetic Info
Genetic Information Nondiscrimination Act (GINA) Protects against use of genetic information in health and employment Does not protect in disability or life insurance or symptomatic disease Active duty military and federal employees are currently exempt from GINA protections Has not been tested in the courts The image is a movie poster from the movie GATTACA in which genetic information was used to discriminate against individuals in that their destiny was supposedly pre-determined by their genes. Although, we may laugh at the idea, the public may have difficulty distinguishing what is Hollywood versus a current practice and thus may have real concerns about these areas. Privacy is a hot button issue across all aspects of medicine but especially in the area of genetics where genetic information can provide insight into future health conditions as well as information on family members’ health. Risks related to the disclosure and use of genetic information have been minimized with the passage of GINA in While the protection GINA offers against genetic discrimination by employers and health insurers has been comforting to many patients, patient advocates and healthcare providers, there are many limitations that warrant highlighting. GINA does not protect against discrimination with respect to: Disability, long term care, or life insurance; members of the military, federal employees, companies with less than 15 employees, symptomatic disease. Further, it is important to point out that GINA has not been tested in the courts. Similar to other civil rights legislation, it may be very hard to prove that discrimination occurred based on the knowledge of genetic information. March 2012 TRiG Curriculum: Lecture 4

Ethics: Prenatal and Pediatric Testing
Pre-implantation genetic diagnosis (PGD) Identify unaffected embryos for implantation What types of genetic disease may be included? Testing of fetuses or minors for adult-onset disorders Generally NOT recommended in the absence of increased risk for pediatric symptoms or treatment options. Even carrier testing may have consequences. In regard to context, although doesn’t apply necessarily apply to the case under discussion (although could if request testing for a daughter or pre-natal testing), there are several ethical issues such as prenatal and pediatric testing. For example: (a) Pre-implantation genetic diagnosis (PGD) for adult onset disorders (b) Prenatal testing or testing of minors for adult-onset disorders. (c) Carrier testing in minors. This information may also be learned via Newborn Screening. Carrier status is important information to know prior to reproductive maturity, however, it may also affect self-concept in negative ways or be misunderstood and/or forgotten. There is general agreement by geneticists and bioethicists, along with published practice guidelines by the American Society of Human Genetics, American College of Medical Genetics and the National Society of Genetic Counselors, that unless testing will influence management decisions in childhood, testing should wait until the child is old enough to make their own informed choice about testing. There is some evidence, however, that minors adjust better to learning genetic information like carrier status through their families based on social development level. Parental authority to know what’s best for their child should also be considered. Guidelines may be found at March 2012 TRiG Curriculum: Lecture 4

The approach Ethical and Legal Issues Pre-test Counseling Informed Consent Testing The next step in the approach is informed consent. Post-test counseling March 2012 TRiG Curriculum: Lecture 4

Informed Consent May be Required
Regulations for genetic tests vary by state May be institutional requirement for review by Risk Management Consent forms include practical issues: What and why testing is being done Risk, benefits, and limitations of testing How results will be conveyed Potential results and implications Effect on relatives Cost and insurance coverage Privacy and confidentiality The responsibility for obtaining and documenting obtained consent may vary by state so the pathologist should be aware of the requirements in their state. Regardless, it is important that the patient be informed about these testing issues so as to make the best decision. Consent forms are considered legal documentation that the patient understands and agrees to testing. In the case of minors or incapacitated adults signature of the legal guardian is required. Some institutions may require that all informed consents be reviewed by Risk Management. For additional information about elements of an informed consent, Please see the updated ASCO recommendations from the Robson et al. article. Robson ME, et al. JCO. 2010; 28: 893 March 2012 TRiG Curriculum: Lecture 4

Genetic testing consent can vary greatly. An example of informed consent from Myriad for genetic testing is a few pages long. The one on the bottom for next-generation sequencing based test to determine fetal risk of Trisomy 21 is two sentences. March 2012 TRiG Curriculum: Lecture 4

The approach Ethical and Legal Issues Pre-test Counseling Informed Consent Testing The next steps are the actual testing and post-test counseling. Post-test counseling March 2012 TRiG Curriculum: Lecture 4

What Geneticists Need to Know about a Test
Is the lab reliable? Coordinate testing Sample collection Communications with lab What are the limitations in terms of answering the clinical question? Detection rate Method/Coverage of target Potential need for follow-up testing To effectively counsel patients and manage their care, medical geneticists and genetic counselors need to know several key things about a given test. (a)They need to know if the testing lab is reputable and how they can coordinate testing. Beyond CAP accreditation and CLIA certification, does the lab have open communications about methods, validations and result interpretation. In other words, who can they call for questions and are those questions answered? Do they meet their stated turn-around-time? (b)Next they need to understand how well the test can answer their clinical question. They need to know what test covers and the methods used so as to order the best test and/or correctly interpret a “normal” test. (c)Along those same lines, it is important to know (ahead if time if possible) what additional testing may be necessary. March 2012 TRiG Curriculum: Lecture 4

Possible test results Positive (known pathogenic mutation) Negative Absence of known pathogenic mutation--Need to discuss residual disease risk Absence of known familial pathogenic mutation--Need to discuss population risks and screening Unknown Significance There is no or limited evidence about the pathogenicity of the identified variant(s) Additional testing and/or future re-interpretation is necessary If our patient tested negative, this would be appropriate (no affected family tested) Breast ca 42 Breast ca 36 d.52 ovarian ca Breast ca 45 This slide describes possible test results. In this case, the proband is unaffected. Without knowing the specific mutation responsible for cancer risk in her family, she may still be at increased risk. This is because if she were to test negative, we would not be able to distinguish if she has not inherited the genetic risk in her family or whether the mutation responsible for the cancer in her family cannot be detected by the test we chose. Unfortunately, relatives may not want to be tested or, as in this case, affected individuals may not be available for testing. March 2012 TRiG Curriculum: Lecture 4

Post-test Counseling Review reasons for testing Review test result(s) Assess comprehension and coping Discuss plan for additional evaluation and/or treatment Follow-up This slide covers aspects of post-test counseling. March 2012 TRiG Curriculum: Lecture 4

Implications of Results: Context Matters
The informational and counseling needs depend on context and indications for testing Examples: Establish or confirm a diagnosis (Gaucher Disease) Reproductive decision-making, carrier testing, fetal testing (cystic fibrosis) Predict risk for future disease (BRCA, Huntington’s Disease) Aid management decisions (e.g., tumor sequencing) Ethical issues vary by context As mentioned previously, the context matters in counseling. Although ideally most aspects were covered in pre-test counseling, the post-test counseling also needs to take into account the context of the results. March 2012 TRiG Curriculum: Lecture 4

Case 1– Single Gene Testing
Patient tests positive for BRCA S1970X (6137C>A) mutation in BRCA2. (Not an Ashkenazi Jewish mutation) Implications for patient Ethical issue Other family members? Breast ca 42 Breast ca 36 d.52 ovarian ca Breast ca 45 The patient test positive and these results have implications for her own prophylactic care. They also have implications for other family members such as this patient’s cousin. Although not close, the patient is encouraged to share her results with her cousin and other at-risk family members. Cousin March 2012 TRiG Curriculum: Lecture 4

Dear [ ]: I recently had genetic testing to help me understand my risk of developing cancer. I was tested for inherited changes (or mutations) in the BRCA1 and BRCA2 genes. My test identified a mutation that runs in our family (relatives related by blood). This test result means that I have Hereditary Breast and Ovarian Cancer syndrome. Fortunately, there are medical options to reduce my risks, which is why knowing about this mutation will be very helpful. It is possible that someone in our family besides me may have a BRCA1 or BRCA2 mutation. I am writing to all of the relatives who may be at risk to also have this mutation. You may want to talk to your doctor about whether genetic testing makes sense for you. Sometimes patient’s may be given letters to help them communicate results to other family members. Here is a condensed version of a sample letter from Myriad to notify family members about a positive BRCA result. March 2012 TRiG Curriculum: Lecture 4

Case 1– Single Gene Testing
The patient’s 35 year old cousin is interested in learning more about her breast cancer risk but decides to pursue testing on her own through a DTC company. Does not include all mutations such as S1970X (6137C>A) mutation in BRCA2. The patient’s 35 year old cousin is informed of the test results and is interested in learning more about her breast cancer risk but decides to pursue testing on her own through a DTC company. While DTC testing has the potential to empower patients, if patients are to interpret their results independently, it is important that they understand the limitations of testing. Some companies test only for the 3 most common BRCA changes among Ashkenazi Jews which are 185delAG, 6174delT, and 5382insC. If this were the case, this woman would have gained no additional information since her family does not carry one of these three mutations. Some DTC tests include a breast cancer risk assessment using variants in genes other than BRCA1 and 2 (such as those identified through GWAS). In that case a negative result would again not provide this patient with any information about her risk of hereditary breast and ovarian cancer syndrome due to the known BRCA mutation in the family. Given the family history and known mutation in the family, any risk algorithm that did not account for these factors would have the potential to significantly under estimate her risk and provide false reassurance. It is important for both patients and their healthcare providers to understand the limitations of testing. March 2012 TRiG Curriculum: Lecture 4

This slide represents a printout from a DTC company. Alleles associated with disease risk were identified by GWAS. How are risks determined? It is actually the same way as any laboratory test. March 2012 TRiG Curriculum: Lecture 4

DTC: A simplistic calculation
“Just another test” in regard to multiplying pre-test probability by an odds ratio to determine post-test probability. Risks are determined multiplying the odds ratio associated with an allele for a given condition/disease state by the population risk gleaned from epidemiological data such as the 12% US Caucasian risk for breast cancer (pre-test probability). Each individual, however, has their own unique pre-test probability that involves factors such family history and environment (such as with BRCAPRO). This calculation also does not take into account how these variants may actually interact with each other. In many cases, the change in absolute risk from the average, population-based risk is minimal. Post-test probability Pre-test probability How about family history? Environment? Ng PC, et al. Nature. 2009; 461: 724 March 2012 TRiG Curriculum: Lecture 4

Risk Prediction: Not easy to do!!
Based on case-control study design = variable results No quality control of associations Need for Clinical Grade Database Ease of use Continually updated Clinically relevant SNPs/variations Pre-test probability assessment Given the odds ratios used for DTC testing results are based on case-control studies, there can be variable results. The table is from a paper showing when a sample from the same patient was sent to different DTC companies, different risks were reported. There is a need for an accurate method to determine pre-test probability and for a clinical grade database to determine which GWAS associations are valid. Ng PC, et al. Nature. 2009; 461: 724 March 2012 TRiG Curriculum: Lecture 4

DTC Genetic Tests: Positive Aspects?
Educate consumers Provide direct access Empower consumers to take charge of their health Motivate behavior change to improve health outcomes Provide confidential testing Although most geneticists are wary of DTC testing, those who favor DTC testing argue that it has the potential for some benefit. March 2012 TRiG Curriculum: Lecture 4

DTC Genetic Tests: Points to Consider
Questionable benefits Qualification of the lab Clinical validity of the test(s) Claims made about the test(s) Privacy Clinical application Appropriateness of tests ordered Interpretation of results False reassurance if “normal” or unwarranted concern if “positive” Forgoing standard treatments Seeking unnecessary treatments Sample swaps at 23 and Me: a cautionary tale By Daniel MacArthur | June 7, | 6:00 a.m. Regardless of one’s opinion about DTC testing, important issues should be discussed. One of the most concerning aspects is the potential for misunderstanding of a test result leading to fear, anxiety and potentially costly or harmful medical procedures and treatments. Also, as pathologists know, strict standards are required for accurate test reporting. The image for this slide shows that errors have already happened with DTC testing. March 2012 TRiG Curriculum: Lecture 4

There is limited data on the actual effect of DTC testing on consumers. This study looked at the effects of a DTC test (SNP chip based, 23 health conditions) on over 2000 individuals. While there was no evidence of anxiety using a standardized instrument there was also no evidence for benefit measured by a change towards helpful habits. No evidence for anxiety No evidence for change Bloss CS, et al. NEJM. 2011; 364: 524 March 2012 TRiG Curriculum: Lecture 4

Geneticist training and professional roles Current and future of reporting and communicating genetic test results Case 1 Single gene tests Direct-to-consumer (DTC) gene chip testing Case 2 Whole genome sequencing The lecture will now move on to case 2. March 2012 TRiG Curriculum: Lecture 4

Case 2 – Risk Prediction with NGS
Patient assessed by cardiologist and genetic counselor due to family history of vascular disease and sudden death 40 yo, no significant past medical history Exercises regularly, no medications Normal clinical exam Normal lipid panel, electrocardiogram, echocardiogram and cardiopulmonary exercise test Social history: highly educated male, professor of bioengineering A paper illustrating risk prediction using next-generation sequencing. The patient was seen by a genetic counselor but what new issues may arise in this setting? Ashley EA, et al. Lancet. 2010; 375: 1525 March 2012 TRiG Curriculum: Lecture 4

This slide shows the patient’s pedigree. Typically, genetic counselors construct a 4-generation pedigree to obtain information about genetic conditions in a family. These pedigrees are often targeted to the reason for referral such as the cardiology-focused one in our case. As another example, a prenatal patient’s pedigree might include things like mental retardation/learning disabilities, congenital anomalies, pregnancy losses and any Mendelian diseases in a family. Information is also collected about chronic or acute medical conditions that have affected family members, the age of onset, and cause and age of death (if relevant). 4-generation pedigree constructed Coronary artery disease, abdominal aortic aneurysm sudden cardiac death in 1st and 2nd degree relatives March 2012 TRiG Curriculum: Lecture 4

Pharmacogenomics may guide care
64 clinically relevant pharmacogenomic variants,12 novel, non-conservative amino acid changing SNPs Most relevant to current care: CYP2C19 variant- clopidogrel Most relevant to future care Variants affecting warfarin dosing, response to statins The authors provided information about several identified variants in the patient that influence drug metabolism. The authors suggest altering care related to clopidogrel in this patient. They suggest that other variants could have relevance for future care but each allele needs to be clinically validated. Even if well characterized, how dosing should be adjusted is not always clear. March 2012 TRiG Curriculum: Lecture 4

Rare Cardiac Variants – Possibly Pathogenic
MYBPC3 Arg326Gln- originally associated with late onset hypertrophic cardiomyopathy Later found in multiple controls Conclusion: probably benign TMEM42 Met41Val- in 1 of 150 probands with ARVD/C Test other family members to help assess relevance? DSP Arg1838His- entirely new variant Several variants were found in known disease genes that have been previously related to Mendelian cardiac risk. One must always consider the quality of the evidence linking a variant to a disease and what do the variant would mean clinically. When interpreting results for patients, genetic counselors/geneticists often consider the same elements as pathologists to interpret the significance. With any variant it is important to assess: Known pathogenic disease associations with the gene Case / control data (i.e. present in cases and not in controls) Is the genetic variant is predicted to result in a biologically damaging amino acid change? How conserved is the wild-type/reference base? What is the prevalence of the variant in control populations, including those of the same ethnicity of the proband? Thus, in order to learn more about the clinical validity of the two potentially deleterious variants additional testing of one or more family members as well as functional studies may be necessary. In this study, 3 variants in genes related to cardiomyopathy were identified. The first occurred in the cardiac myosin binding protein C gene (an arginine to glutamine substitution). Originally this variant was associated with late onset hypertrophic cardiomyopathy. Importantly, however, the interpretation analysis did not stop there. Further study showed it was subsequently found in multiple control samples. It is suspected this variant is probably benign. There was limited information available about TMEM42 variant. It has been previously reported in 1/150 probands with arrythmogenic right ventricular dysplasia/ cardiomyopathy and not in controls. The authors used the family history to help interpret the significance of this finding. A 1st cousin of the proband apparently meets minor criteria for ARVD/C and his son died suddenly in his teenage years. Testing to determine if the variant travels with disease in the family can potentially rule it out as being causative, but cannot definitively rule it in. It can only provide more positive evidence of a true association. A newly reported (aka novel) variant was identified in the DSP gene. Variants within DSP have previously been associated with sudden cardiac death. Databases were used to assess conservation and functional impact of this variant. In vivo studies could provide additional insights, but will require additional time and resources. Similar to above, testing could be performed in other relatives to provide more evidence for or against its clinical significance. March 2012 TRiG Curriculum: Lecture 4

Unexpected Findings 3 variants in 2 genes associated with hemochromatosis No family history No current clinical evidence of disease in patient How should management be changed? Serum ferritin monitoring? Gene variant implicated in parathyroid pathology Osteoarthritis in family and knee pain in patient related to this? There were unexpected findings related to hemochromatosis and parathryoid pathology. Although one could make the argument that there are no incidental findings in WGS, based on the clinical indication of cardiac arrhythmia, unintended findings were identified. It is unclear whether or not these findings should alter management. For example, 3 variants in 2 genes associated with hemochromatosis were found, but there is no family history of this disorder. Hemochromatosis is known for its reduced penetrance and variable expressivity. The patient does not demonstrate evidence of disease but this raises the question of whether or not monitoring of ferritin should be implemented as a preventive screen. March 2012 TRiG Curriculum: Lecture 4

Clinical Risk determination (prevalence X post test probability = clinical risk) Pre-test probability Post-test probability This figure shows the pre- converted to post-test probabilities based on the genomic findings. The pre-test probabilities for this study were, similar to DTC testing, based on general population prevalence. The same issues with accurate pre-test probability apply as general population data will not apply to the individual for calculating pre-test probability. As has been discussed, there are many additional factors involved in determining risk (environment, family history) such as taken into account by the BRCAPRO breast cancer program. In addition, all the odds ratios for calculations are based on GWAS which have the limitations mentioned previously. There is, again, a need for a consensus among laboratory and genetics professionals regarding interpretation of these variants and the establishment of a clinical grade database March 2012 TRiG Curriculum: Lecture 4

Pre-test Probability: Population vs Individual
On the right is how the pre-test probabilities were calculated for this study (average population prevalence). Of course, pre-test probability is more complicated as noted by the factors taken into account by BRCAPRO. Parmigiani G, et al. Ann Intern Med. 2007; 147: 441 Ashley EA, et al. Lancet. 2010; 375: 1525 March 2012 TRiG Curriculum: Lecture 4

“No methods exist for statistical integration of such conditionally dependent risks” Strength of association based on # of Medline articles A further problem is that there is no way to integrate different risks. As an example, how do cholesterol, smoking and a SNP (determined through GWAS) all interact to predict risk of coronary heart disease. As there are no statistical methods, the integration/strength of association figure from this study was based on the number of Medline articles showing a relationship. This case illustrates some of the complexity that goes along with interpreting these data in a clinical scenario. It is important to remember that: Statistical models to combine risks are still lacking. Although odds ratios are available for certain variants, a priori risks are hard to incorporate. It is difficult to quantify things like family history There is a need to incorporate environmental risk information How do you combine risks with overlapping disease states? (e.g., if one has a higher risk for type II diabetes, which can contribute to heart disease, how is this information incorporated? Epidemiologic data on population risks is available for many, but not all, diseases. Which diseases should be examined? Even if relative risks are significant, absolute risks may remain low; therefore benefits of intervention are questionable. March 2012 TRiG Curriculum: Lecture 4

To the Nth power for genomics
Ethical and Legal Issues Pre-test Counseling Informed Consent Testing The process for patient communication for genomic testing uses similar principles as for single-gene testing but to the Nth power. There is an increased volume of information in regard to the possibilities that warrant discussion in pre-test counseling and in potentially significant results to discuss in post-test counseling. Post-test counseling March 2012 TRiG Curriculum: Lecture 4

Counseling: Genomic Testing
Same principles Setting appropriate expectations WGS is limited by our current biological understanding Communicating multiple complex results effectively Prioritization of most significant results Timing of communication (how much at once?) Method of communication (written, verbal, electronic) Incidental findings Familial implications of results Need for ongoing communication as interpretation of results evolves The same principles and processes of traditional genetic counseling also apply to new whole genome/exome testing but more complex. Appropriate expectations must be set with a plan regarding disclosure. Keep in mind, the same issues can arise with tumor sequencing. Specific issues: Chance of incidental findings Disease risks not related to initial testing indication Mis-attributed parentage Reporting to other family members (e.g., BRCA2 variant may not be appropriate to disclose to minor male, but could be very important to his parents, one of whom also carries the variant.) In addition there are some very practical issues that must be considered including: How does a clinician prepare an individual or a family? It is very important to be open about the limitations of current genomic testing. Our understanding of genetic disease and how variants interact is very limited. There is a very good chance that WGS will not be able to determine the answer to the clinical questions posed. It will take continual analysis and new discoveries to completely understand the results. Also, based on the current state of the science there will be errors and many variants of uncertain significance detected in WGS. What is the responsibility of the clinician or the laboratory to continue to monitor the literature around each of those variants and update the patient as new information is found. If this is not done what are the potential risks, if this is done, how will this be paid for and to what extent does this responsibility go? Do you need to track down a patient who has moved and not provided an updated address? The next of kin when a patient is known to have died but new information which affects the family is now available? March 2012 TRiG Curriculum: Lecture 4

Counseling: Genomic Testing
Difficulties in interpretation Large amount of data/results with limited models for clinical interpretation Integration with family history, environmental risks Error rates, validation processes If testing is done, a very large volume of results will be generated. How can we interpret those results? As noted previously, different risks can be interpreted based on differing pre-test probability and variants analyzed (image of when a sample from the same patient was sent to different DTC companies, different risks were reported). Few models exist for integrating all traditional risk factors (family history, environment) with test results There can be error rates with the laboratory. Should all results be validated with more traditional methods? Ng PC, et al. Nature. 2009; 461: 724 March 2012 TRiG Curriculum: Lecture 4

Ethics: To the Nth Power
Informational overload and patient comprehension Patient autonomy to learn/refuse results What information should be returned? Lab and clinical liabilities if results are not disclosed or genomic regions analyzed? How to store results in an accessible but private manner? What information to return when testing minors? If results are fully disclosed then the patient could receive large amounts of information on wide variety of conditions and disorders Carrier status for recessive conditions Well validated pathogenic variants with known interpretation and management options (e.g. BRACA) Well validated pathogenic variants for which nothing can be done (e.g. Huntington disease) Well validated risk associations (e.g. ApoE and Alzheimer disease) Unvalidated associations Variants of unknown significance Variants for non-medical traits (e.g. hair color) What are the medical-legal aspects of what needs to be disclosed and for continued reporting to patients as new associations are identified? These issues may be compounded in pediatric cases. In the event that WGS reveals the minor patient is homozygous for the APOE4 allele associated with Alzheimer’s disease, is this information that should be conveyed to his parents, the 12 year old patient himself? What about variants of uncertain significance, should those be highlighted as potential future medical issues if they occur in genes associated with known diseases? The issues must be discussed in advance of testing for any individual patient. On a broad scale, scientists and ethicists are working to consider policies which may influence how the onslaught of WGS data should be handled and delivered. March 2012 TRiG Curriculum: Lecture 4

Genomics Requires New Clinical Models
Lengthy, multiple pre-/post-test sessions Reimbursement for broad-based testing Data reporting and storage in medical record systems Informed consent “The patient received education and counseling before signing the consent form and throughout testing and follow-up.” The figure on the right shows a model for whole-genome testing and reporting but each step has significant complexity. Clearly, discussion of whole genome technology and relevant informed consent issues will be time-consuming. Interpretation of results and reporting is complicated not only for the laboratory, but also for the clinicians charged with explaining this to the patient and arriving at evidenced-based management recommendations. How will this all be done in a cost effective manner? Interpretation in the clinical context may also require collaboration between multiple specialties (ie pathologist, genetics professionals, internist, and specialists). Access to this type of comprehensive care will be limited. Reimbursement for preventive care and counseling services is historically low. The paper did not go into details on the counseling the patient received and the nature of the informed consent (quote). What should this consent consist of? What can we use from traditional consent forms for genetic testing? Ashley EA, et al. Lancet. 2010; 375: 1525 Roychowdhury S, et al. Sci Transl Med. 2011; 3: 111ra121 March 2012 TRiG Curriculum: Lecture 4

Summary: To the Nth Power
Core principles apply Huge amount of data Difficulties in interpretation Reimbursement Multiple ethical issues Informed consent Ethical and Legal Issues Pre-test Counseling Informed Consent Summary of communicating with the patient in the genomic era. Testing Post-test counseling March 2012 TRiG Curriculum: Lecture 4

Multidisciplinary Teams Needed
Modern medical technology and practice requires a multidisciplinary approach to medical practice. Greater interaction needed between Pathologists, Genetic Counselors and Medical Geneticists A key point is that the genomic era necessitates even greater need for a multidisciplinary approach particularly in regard to translating the sequence data into an actionable clinical interpretation for the ordering physician and their patient. Roychowdhury S, et al. Sci Transl Med. 2011; 3: 111ra121 March 2012 TRiG Curriculum: Lecture 4

What will be the pathology report of the future?
Ethical issues Informed consent Integrated data interpretation What will the pathology report of the future look like? We will likely need increased integration of both AP (histology) and CP (genetic testing) components and may also include ethical issues. March 2012 TRiG Curriculum: Lecture 4

Lecture IV: Genomic Medicine: Communicating with the Patient

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Lecture IV: Genomic Medicine: Communicating with the Patient

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