November 2013 by San Francisco Marin Medical Society

SAN FRANCISCO MEDICINE J O U R NA L O F T H E S A N F R A N C I S C O M E D I CA L S O C I E T Y

Genetics

Nature, Nurture, and Advances in Medical Care Everyday Epigenetics Stopping Hereditary Breast Cancer Before It Starts

A Day in the Life of a Geneticist Are Your Patients Ready for Pharmacogenomic Testing?

VOL. 86 NO. 9 November 2013

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IN THIS ISSUE

SAN FRANCISCO MEDICINE

November 2013 Volume 86, Number 9

Genetics: Nature, Nurture, and Advances in Medical Care FEATURE ARTICLES

MONTHLY COLUMNS

12 A Day in The Life of a Geneticist: The Role of Genetics and Genomics in Health Care Emily Chen, MD, PhD

Membership Matters

Ask the SFMS

16 Everyday Epigenetics: From Molecular Intervention to Public Health and Lifestyle Medicine Martha R. Herbert, MD, PhD

Presidentâ&#x20AC;&#x2122;s Message Shannon Udovic-Constant, MD

10 SFMS Advocacy Activities

13 Hereditary Breast Cancer: Stopping It Before It Starts Pamela Lewis, MD

19 Pharmacogenomic Testing: Are You or Your Patients Ready? Alan H. B. Wu, PhD 21 Commercialized Genomics: Caveat Emptor Steve Heilig, MPH

Of Interest

23 Public Health Update: Syphilis in San Francisco, 2000 to 2013 Joe Engelman, MD, MPH, and Stephanie Cohen, MD, MPH

11 Editorial Gordon Fung, MD, PhD

24 Medical Community News 26 In Memoriam Nancy Thomson, MD 26 Classified Ads

Welcome New Members The SFMS would like to welcome the following members:

Editorial and Advertising Offices: 1003 A Oâ&#x20AC;&#x2122;Reilly Ave. San Francisco, CA 94129 Phone: (415) 561-0850 e-mail: adenz@sfms.org Web: www.sfms.org Advertising information is available by request.

MEMBERSHIP MATTERS Activities and Actions of Interest to SFMS Members

ing Californians with a diverse selection of plans from which to choose. The new plans will go into effect on January 1, 2014, and will offer lower out-of-pocket expenses for deductibles and copays. Preexisting conditions will no longer be taken into consideration, lifetime limits are eliminated, and subsidies will be available for individuals earning up to $46,000 and for families with incomes of up to $94,200. SFMS, in partnership with the CMA and Covered California, is in the process of developing several resources to help educate physicians on the exchange and ensure that they are aware of important issues related to exchange plan contracting. A Covered California FAQ can be found on page 7. Please visit the SFMS website for additional resources and upcoming event information.

Paradise Internist Elected as CMA President CMA Delegates Set Policy at Annual Meeting The SFMS Delegation, along with 500 California physicians, convened in Anaheim for the 2013 CMA House of Delegates. The CMA HOD is an annual conference where all fifty-three California counties, representing all modes of practice, meet to discuss issues related to health care policy, medicine, and patient care, and to elect CMA officers. The delegation submitted sixteen policy proposals for consideration and almost all were adopted, albeit some in watereddown form. CMA will now support graphic image warning labels on tobacco packaging; encourage and promote the reporting of immunizations to the California Department of Public Health for purposes of vaccination, disease control, and prevention; advocate for fair reimbursement of telephonic or electronic patient management; endorse the National Transportation Safety Board’s recommendation to reduce the legal blood alcohol limit for operating a motor vehicle to .05 percent; support efforts to enable usability and interoperability of EHR systems and facilitate the exchange of health information among health care providers; and more. A detailed report will appear in the December issue of San Francisco Medicine.

Covered California Enrollment Launch and Available Resources Beginning October 1, Californians have the opportunity to purchase health coverage through the state’s new health insurance exchange, Covered California. Twelve regional and statewide health plans are participating in Covered California, provid4 5

San Francisco Medicine November 2013

Richard E. Thorp, MD, FACP, was elected as the 2013–2014 president of the CMA at the House of Delegates in October. Dr. Thorp is the president/CEO of Paradise Medical Group, Inc., a physician-owned, multispecialty primary care group. He has been a member of CMA since 1985 and has served in a number of leadership roles. Prior to his post as president-elect, a position he held for the past year, Dr. Thorp was the chair of CALPAC, and he previously served on the CMA Committee on Medical Services and Committee on Managed Care. “I will not compromise the honor of this profession for the victory of the moment. I will not capitulate or surrender. I will fight to protect this profession you hold so dear,” Dr. Thorp said as he addressed the nearly 500 physician delegates in attendance at HOD. “In this critical time, the House of Medicine cannot afford to do business as usual. We cannot afford the status quo. We must come with the audacity to create a dream and a vision for the future of medicine and health care in California.”

Pledge Your Commitment to Medicine and Renew Your Membership Today

SFMS would like to thank our 1,600-plus members for their support of the local medical society this year. Because of your support and participation in organized medicine, SFMS continues to be the preeminent physician organization championing the case of physicians and their patients as we face the many challenges of these changing times. Please take a moment to renew your support of SFMS by remitting payment for your 2014 dues today. There are three easy ways to renew your dues again this year: • Mail/fax in your completed renewal form. • Renew online at sfms.org using your credit card. • Enroll in the Easy Pay (quarterly installments) Automatic Dues Renewal Plan by contacting SFMS at (415) 561-0850 or membership@sfms.org. www.sfms.org

Physicians Renewing Licenses in October and November May Experience Delays The Department of Consumer Affairs is currently transitioning to a new online licensing and enforcement system, which may cause disruptions to services such as cashiering for both online and mail renewals. Consequently, the Medical Board of California encourages physicians whose medical licenses expire in October and November to submit renewal applications in advance. In doing so, they will avoid licensing delays that could affect their practices. Renewal notices are sent out ninety days in advance of the licensee’s expiration date. If you have already submitted your renewal application but have not received confirmation of it having been successfully processed, SFMS/CMA recommend contacting the medical board for updates on the status of your license. If your license is expiring within two weeks and you have not yet submitted your renewal application to the medical board, do not submit your renewal to the P.O. Box listed on the renewal as it may not be processed before the expiration date. For faster service that allows expedited processing, the medical board suggests submitting the renewal application to Medical Board of California, 2005 Evergreen Street, Suite 1200, Sacramento, CA 95815. The medical board expects to have the new online system available at the beginning of November but does not guarantee the launch date. Any questions or concerns should be directed to the medical board at (916) 263-2382 or webmaster@mbc.ca.gov.

The Northern California Chapter of the American College of Surgeons (ACS) to Host Summit Focused Upon Improving Emergency Surgical Care

Health care leaders from across the Bay Area are invited to take part in a community discussion around improving surgical quality, drawing on valuable lessons learned in the successful delivery of emergency and trauma care at multiple local hospitals after the Asiana Airlines accident. The ACS Surgical Health Care Quality Forum Northern California will discuss effective strategies to strengthen patient care and produce better outcomes through enhanced emergency care coordination. The event is scheduled for January 14, 2014, from 8:30 a.m. to 10:30 a.m. Further details, including the official RSVP invite, will be posted on http://www.InspiringQuality.FACS.org in the coming weeks.

Network with Colleagues at St. Mary’s Medical Center Progressive Dinner

St. Mary’s annual Progressive Dinner will take place on November 13 from 5:00 p.m. to 7:30 p.m. The event will highlight the new Sister Diane Grassilli Center for Women’s Health and other facilities. For more information or to RSVP, please contact Lydia Lee at (415) 750-5868 or Lydia.Lee@dignityhealth.org.

Complimentary Webinars for SFMS Members

CMA offers a number of excellent webinars that are free to SFMS members. Members can register at www.cmanet.org/events. • December 4: Medicare: 2014 New Rules • 12:15 p.m. to 1:15 p.m. • December 5: ICD-10 Documentation for Physicians: Part 1 • 12:15 p.m. to 1:15 p.m.

www.sfms.org

November 2013 Volume 86, Number 9 Editor Gordon Fung, MD, PhD Managing Editor Amanda Denz, MA Copy Editor Mary VanClay

EDITORIAL BOARD Editor Gordon Fung, MD, PhD Obituarist Nancy Thomson, MD Stephen Askin, MD Erica Goode, MD, MPH Toni Brayer, MD Shieva Khayam-Bashi, MD Linda Hawes Clever, MD Arthur Lyons, MD John Maa, MD Chunbo Cai, MD

SFMS OFFICERS President Shannon Udovic-Constant, MD President-Elect Lawrence Cheung, MD Secretary Man-Kit Leung, MD Treasurer Roger S. Eng, MD Immediate Past President Peter J. Curran, MD SFMS STAFF Executive Director and CEO Mary Lou Licwinko, JD, MHSA Associate Executive Director for Public Health and Education Steve Heilig, MPH Associate Executive Director for Membership Development Jessica Kuo, MBA Director of Administration Posi Lyon Administrative Assistant Ariel Young BOARD OF DIRECTORS Term: Jan 2013-Dec 2015 Charles E. Binkley, MD Gary L. Chan, MD Katherine E. Herz, MD David R. Pating, MD Cynthia A. Point, MD Lisa W. Tang, MD Joseph Woo, MD

Term: Jan 2011-Dec 2013 Jennifer H. Do, MD Benjamin C.K. Lau, MD Keith E. Loring, MD Ryan Padrez, MD Terri-Diann Pickering, MD Adam Schickedanz, MD Rachel H.C. Shu, MD

Term: Jan 2012-Dec 2014 Andrew F. Calman, MD John Maa, MD Edward T. Melkun, MD Justin V. Morgan, MD Kimberly L. Newell, MD Richard A. Podolin, MD Elizabeth K. Ziemann, MD CMA Trustee: Shannon Udovic-Constant, MD AMA Delegate: H. Hugh Vincent, MD AMA Alternate: Robert J. Margolin, MD

November 2013 San Francisco Medicine

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San Francisco Medicine November 2013

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Covered California

Covered California, the state health insurance exchange, will serve more than five million uninsured Californians, beginning January 1, 2014. It will be the cornerstone of the reform efforts called for under the Patient Protection and Affordable Care Act.

What is Covered California?

Covered California is the new marketplace where Californians can compare and purchase health coverage. Through Covered California, many patients will be eligible for financial assistance to help pay their premiums and even co-pays. Through Covered California, individuals and small businesses can compare different health insurance companies and learn whether they qualify for federal subsidies and tax credits. Californians will also be able to find out if they are eligible for low-cost or no-cost health coverage through Medi-Cal.

How will Covered California impact my practice?

The impact on physician practices will vary greatly depending on the mix of patients in your practice and the extent to which you contract with Covered California plans. Millions of previously uninsured Californians will now be eligible for health insurance through Covered California and Medi-Cal. Your patients with employer-sponsored coverage are not likely to see significant changes in their coverage.

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Individuals with incomes up to $45,960 and a family of four with an income up to $94,200 may be eligible for premium assistance.

Will my Covered California patient be able to continue to see me?

You will have to be contracted with a Covered California plan and your patient will have to select that plan. Each health insurance plan has a specific list of doctors and hospitals that are considered in-network providers for covered services. Patients should be advised to verify with the individual plan that a particular doctorâ&#x20AC;&#x2122;s or hospitalâ&#x20AC;&#x2122;s services will be covered under that plan. Covered California will provide a searchable online directory so that patients can see which health plan networks contain a particular doctor or hospital.

How can a patient apply for Covered California coverage or Medi-Cal?

Open enrollment will continue until March 31, 2014, but patients must enroll in a plan by December 15, 2013, for coverage to begin January 1, 2014. In subsequent years, open enrollment will run from October 15 through December 7. Patients can apply for a Covered California health insurance plan online at www.CoveredCA.com or by calling (800) 300-1506.

Where can I obtain additional information about Covered California?

SFMS, in partnership with the CMA and Covered California, is in the process of developing several resources to help educate physicians on the health benefits exchange and ensure that members are aware of the important issues related to exchange plan contracting. Please visit the SFMS website, www.sfms.org, to view a list of upcoming luncheon seminars for physicians and practice managers about Covered California and its impact on medical practices. Additionally, the CMA has created a dedicated exchange news page at http://www.cmanet.org/ issues-and-advocacy/cmas-top-issues/aca/exchange-news/ to include the latest updates about Covered California.

Which patients can buy coverage through Covered California?

Legal California residents, except for currently incarcerated individuals and legal minors, are eligible to buy insurance through Covered California. If a patient has access to affordable health insurance through an employer or government program, he or she can purchase coverage through Covered California but may not qualify for financial assistance.

Which patients are eligible for Covered California subsidies to purchase coverage?

Premium assistance is available to individuals and families who meet certain income requirements and do not have access to affordable, adequate health insurance through their employers. Eligibility for premium assistance is based on family income and the number of people in the family. The size of the premium assistance is calculated on a sliding scale, with those who make less money getting more financial assistance. www.sfms.org

November 2013 San Francisco Medicine

SAN FRANCISCO MEDICAL SOCIETY

Annual Gala • January 16, 2014 •

Be a part of the biggest membership event of the year! Come together with many of San Francisco’s most influential stakeholders in the medical community to celebrate SFMS’ 146 years of physician advocacy and camaraderie. President-Elect Lawrence Cheung, MD and the San Francisco Medical Society request the pleasure of your company at the

Asian Art Museum Network with colleagues, meet SFMS leaders, and enjoy a private viewing of the Asian Art museum’s collection galleries

200 Larkin St, San Francisco, CA 94102 • Thursday, January 16, 2014 6:30 p.m. to 9:00 p.m. • Black Tie Optional Guests are treated to an exquisite reception with elegant hors d’oeuvres and libations Invitations will be mailed out in early December to SFMS members For more information: www.sfms.org/events.aspx This is a member-only event. SFMS members may purchase tickets (for themselves and guests, and/or sponsor a medical student) via the SFMS website.

San Francisco Medicine November 2013

www.sfms.org

PRESIDENT’S MESSAGE Shannon Udovic-Constant, MD

Bigger Than Genes In preparation for this month’s San Francisco Medicine, I was thinking about genetics and the enormous amount of information that will soon be available to our patients about their disease risks. In a recent survey following an NPR segment discussing whether individuals would want to know their genome, 80 percent of respondents said yes and 72 percent said they would want to know everything even if they are predisposed to an incurable disease. Wow. This is something that I will need to educate myself on to be able to counsel families on the benefits and risks of finding out this information. My national specialty organization, the American Academy of Pediatrics, has this as one of its strategic priorities, recognizing the need to educate its members. I look forward to this new age of medicine. Yet I then come back to the age-old issue of nature versus nurture. We know that a large amount of predetermined fate is passed through our genes. Yet we continue to learn that aspects of our environment act on these genes to change their expression. Thinking about the recent California Medical Association annual meeting, I realize that there can be a tendency to blame individuals for certain things that are really the result of their environment. One physician, for example, wanted to tax individuals who are obese. This idea was soundly defeated. Some personal choice is involved in getting to an unhealthy weight, but as a pediatrician, I see that most of the overweight young people I meet don’t have much choice in the matter. They attend schools that offer thirty minutes of physical education twice a week. They live in neighborhoods where it is not safe to play outside. They have two parents working full-time who just don’t have the energy to prepare a healthy meal for dinner at the end of a long day, so they drive through for fast food instead. We are also learning about the association of food insecurity with obesity. If a family is on food stamps, they will have money for food at the beginning of the month and will eat well in those first few days. Then, as the month progresses, food becomes scarce. At the beginning of the next month they can, again, eat a lot. The cycle of food deprivation leads to overeating. The association of poverty and poor health is well established. Dr. Anthony Iton, the senior vice president of Healthy Communities for the California Endowment, asserts “that the only sustainable approach to eliminating health inequities is through the design of intensive, multisectoral, place-based interventions that are specifically designed to identify existing assets and build social, political, and economic power among a critical mass of community residents in historically underresourced communities.” Dr. Iton has further stated, “In America, wealth pretty much equals health.” We know that having a good education can help someone www.sfms.org

break the cycle of poverty. Unfortunately, our poor neighborhoods usually lack access to a good education. I just finished the book Fire in the Ashes by Jonathan Kozol, a teacher with an interest in social psychology. He shares what happened to many of the children he first met twenty-five years ago. Some of these stories are heartbreaking. Yet some of his former students were able to succeed despite the many challenges working against them. The ones who were able to do well had some extraordinary charity bestowed on them, such as a minister shepherding them toward a local prep school under a scholarship, or a benefactor paying for their tuition to attend a better school. Kozol states, “Charity and chance and narrow selectivity are not the way to educate the children of a genuine democracy.” Instead, systematic equity should be the hallmark of education for children. The question that follows is how much responsibility do we, as physicians, have to turn our attention to addressing the educational system and poverty in this country? A group of pediatricians in California has decided that this is of utmost importance to the health of their patients. It has now become a focus for AAP California. It is a daunting task, and yet it is energizing. I look forward to bridging this work with SFMS and CMA. What can you do to begin to address these issues? In his inaugural address in 1961 John F. Kennedy stated, “If a free society cannot help the many who are poor, it cannot save the few who are rich.”

November 2013 San Francisco Medicine

San Francisco Medical Society

Advocating for Physicians and Patients The San Francisco Medical Society (SFMS) has been a champion for community health issues since its inception in 1868. As the only medical association in San Francisco representing the full range of medical specialties and interests, many projects and activities that have begun here have gone on to have implications for the state and the nation. Beyond the broad and deep resources devoted by the CMA to representing physicians in the halls of state politics and in providing many useful practice management resources, here are some highlights from the SFMS community health agenda.

SFMS Community Health Activities

Universal Access to Care: SFMS leaders have long advocated

End-of-Life Care: SFMS leaders have developed numerous

policy and educational efforts to improve care toward the end of life, including promulgation of the Physicians Orders for LifeSustaining Treatment medical order.

Rebuilding and Preserving San Francisco General Hospital: SFMS spokespersons took a lead in both advocating for

full funding of the seismic rebuild and acting on the mayoral committee to advise where and how that would best occur.

Blood Supply: SFMS has long been a partner of the Blood Centers of the Pacific and continually seeks to help increase donations there.

that every San Franciscan should have access to quality medical care, with ongoing, vigilant efforts to preserve programs and prevent cuts in Medi-Cal reimbursement. Our representatives served on the Mayoral Task Force that designed the Healthy San Francisco program, and SFMS joined in the lawsuits to preserve that program as well. SFMS members advocated for, and even created, community clinics dating back to the original Haight-Ashbury Free Clinics in the 1960s.

Organ Donation: SFMS has been a leader in seeking improved donation of organs to decrease waiting lists due to the shortage of organs, via education and new polices regarding consent and incentives for organ donation.

roles in the banning of tobacco smoking in San Francisco restaurants, ahead of the rest of the state and nation; we advocate for ever-stronger protections from secondhand smoke, for removal of tobacco products from pharmacy settings, for higher taxes on tobacco products, and more. SFMS signed onto an amicus brief in support of upholding San Francisco’s law banning the sale of tobacco in pharmacies.

Drug Policy: SFMS has been a leader in exploring and advocat-

Anti-Tobacco Advocacy: SFMS advocates were in leadership

HIV Prevention and Treatment/Hepatitis B: The SFMS

was at the center of medical advocacy for solid responses to the AIDS epidemic, being among the first to push for legalized syringe exchange programs, appropriate tracking and reporting, optimal funding, and more. SFMS is a partner in the Hep B Free program in San Francisco and in educating physicians and patients on prevention and treatment of hepatitis B.

Schools and Teen Health: SFMS helped establish and staff a citywide school health education and condom program, removed questionable drug education efforts from high schools, and worked on improving school nutritional standards; it provides ongoing medical consultation to the SFUSD school health service. In addition, SFMS has authored a resolution allowing minors to receive vaccines to prevent STIs without parental consent. Environmental Health: SFMS’s many efforts include establishing a nationwide educational network on scientific approaches to environmental factors in human health and advocating for the reduction of mercury, lead, and air pollution exposures. Reproductive Health and Rights: SFMS has been a state and national leader in advocating for women’s reproductive health and choice, including access to all medically indicated services. 10 San 11 SanFrancisco FranciscoMedicine Medicine November November2013 2013

Operation Access: SFMS is a founding sponsor of this local or-

ganization providing free surgical services to the uninsured and has provided office space, volunteers, and funds.

ing new and sound approaches to drug abuse, including some of the first policies regarding syringe exchange, medical cannabis, and treatment instead of incarceration. We were integral in the development of the CMA’s landmark report on decriminalization and regulation of cannabis.

Medical Ethics: SFMS has developed and promulgated forward-

looking policies and approaches regarding end-of-life care, patient directives, physician-assisted dying, and other topics of interest to patients, physicians, policy makers, and the general public.

Partnerships: SFMS works closely with many local specialty and health organizations, such as the San Francisco Department of Public Health, San Francisco Emergency Physicians Association, San Francisco Pediatric Council, San Francisco Community Clinic Consortium, West Bay Hospital Conference, Chinese Community Health Care Association, and others.

“I was an SFMS member for almost fifty years until I retired and always saw them as an important and often progressive voice in organized medicine on many crucial issues.” —Philip R. Lee, MD, UCSF Chancellor Emeritus and U.S. Secretary of Health “The SFMS helped save the Haight Free Clinic from the start, and I’ve been a loyal member ever since. So much of state and national impact has come from here and the SFMS has helped in many ways.” —David Smith, MD, founder, Haight-Ashbury Free Medical Clinics SFMS: An advocate for physicians and their patients www.sfms.org

EDITORIAL Gordon Fung, MD, PhD

Genetics and Medicine If there is any one area of medicine exploding right now it is genetics and the new ways genetics allow us to approach medical disease. As medical students, we were taught about Mendel’s Principles of Heredity, also known as Mendelian Inheritance. This set of two was concepts developed by an Austrian monk through his work with 5,000 garden peas. We had as much difficulty understanding its application to human genetics as he did in 1865. His laws were developed looking at the phenotypic expression of the gene mix that allowed him to summarize his findings into two laws—The Law of Segregation and The Law of Independent Assortment. The Law of Segregation states that every individual possesses a pair of alleles (assuming diploidy) for any particular trait and that each parent passes a randomly selected copy (allele) of only one of these to its offspring. The offspring then receive its own pair of alleles for that trait. Interactions between alleles at a single locus are termed dominance and these influence how the offspring expresses that trait (e.g. the color and height of a plant, or the color of an animal’s fur). The Law of Independent Assortment, also known as “Inheritance Law”, states that separate genes for separate traits are passed independently of one another from parents to offspring. That is, the biological selection of a particular gene in the gene pair for one trait to be passed to the offspring has nothing to do with the selection of the gene for any other trait. Using these laws, medicine was able to determine some classic autosomal dominant diseases—Familial Hypercholesterolemia, Polycystic Kidney Disease, Hereditary Spherocytosis, Marfan’s Syndrome, and Huntington’s disease. Autosomal recessive disorders included sickle cell disorders, cystic fibrosis, Tay Sachs disease, Phenylketonuria, and lysosomal, and lipase deficiency disorders. And X-linked disorders such as Duchenne Muscular Dystrophy, and Hemophilia. Some of these diseases are rare and a physician can go through an entire career without having patients with these disorders. However, as technology advanced and we were able to crack the genetic code and study diseases for genetic variations, medicine was able to identify significant genetic differences in common diseases like breast cancer, atrial fibrillation, long QTc Syndromes, and cardiomyopathies. Companies were spawned to be repositories of tissues and blood samples to determine the genetic makeup of different diseases, e.g., breast cancer, melanoma. Patients’ blood could be sampled for genetic differences to predict an individual’s response to specific medication in a new field called pharmacogenomics. Geneticists are frequently consulted in patients with cardiomyopathy or genetic diseases for diagnosis of the genetic defect that may be responsible for the disorder. Genetic counselors work together with the geneticists to help families and www.sfms.org

the patients understand the disorder and further test family members for the diseases. They also recommend testing of family members who might be at risk for the disease and help them sort through the latest research in preventing progression or development of or treatment of the disorder. A recent development in this field is a new company, 23andME, a privately held personal genomics and biotechnology company based in Mountain View, California that provides rapid genetic testing. The company is named for the 23 pairs of chromosomes in a normal human cell. Their personal genome test kit was named “Invention of the Year” by Time magazine in 2008. 23andMe began offering DNA testing services in November, 2007, the results of which are posted online and allow an assessment of inherited traits, genealogy, and possible congenital risk factors. Customers provide a 2.5 ml saliva sample that is analyzed on a DNA microarray (manufactured by Illumina), for 960,000 specific single-nucleotide polymorphisms (SNPs). An eventual goal is to provide whole genome sequencing. New York and California unsuccessfully attempted to block such tests (provided by 23andMe as well as other companies) under the grounds that they were not properly licensed and attempted to require tests to be conducted only when ordered by a physician. By August 2008, 23andMe had received licenses that allowed them to continue to do business in California. This month’s theme of genetics and medicine discusses some of the emerging issues in this field. From the day in the life of a geneticist by Emily Chen to the issues of hereditary breast cancer by Pamela Lewis, these discussions just scratch the surface of this new field of medicine. Dr. Alan Wu discusses pharmacogenomics and how the FDA recommends using a person’s genetics makeup to prescribe the correct medicine and dose of certain drugs. Dr. Martha Herbert gives an entire background on everyday epigenetics. And our own Steve Heilig gives a cautionary perspective. We hope this collection of stories will help you start thinking about genetics and your practice as this growing field continues to make its way into all of our specialties. November 2013 San Francisco Medicine

Genetics

A Day in the life of a geneticist The Role of Genetics and Genomics in Health Care Emily Chen, MD, PhD Most people donâ&#x20AC;&#x2122;t realize how exciting and rewarding a geneticistâ&#x20AC;&#x2122;s work is. A geneticist is a puzzle solver, diagnostician, detective, genomicist, scientist, assessor of risk, information seeker, empathizer, supporter, educator, and, occasionally, an epidemiologist, ethicist, and bioinformaticist. Specializations within the field include dysmorphology and cytogenetics and biochemical, metabolic, molecular, prenatal, and cancer genetics.

The explosion of knowledge about developmental and enzymatic pathways, patterns of malformation, gene function, epigenetic factors, and the rapid identification of genes is now more than ever obligating us to think about how medical genetics moves the future of medicine forward. We know that the role of genes in health is important, but genes obviously do not tell the whole story. Certainly choice, chance, and environment play important roles also. The geneticist can advise whether or not to do a genetic test, decide which laboratory to send the test to, determine which methodology of the testing is optimal, and help the patient understand the implications of a particular diagnosis or the results of a test. The geneticist can also determine who is the best member of the family to have genetic testing first and help sort out the complexities and nuances of genetic testing results. A geneticist usually works closely with a genetic counselor, who has specialized graduate training to provide information and support to families who have members with birth defects or genetic disorders, and to families who may be at risk for a variety of inherited conditions. A typical genetics visit includes a review of the medical and family history (including contructing a detailed family pedigree); review of pertinent medical records (for patient and family members) and lab results; physical exam with special attention to dysmorphology and any features unusual for the patient and his/her family; database and website searches; a discussion about diagnoses and what is known about the genetics of the patientsâ&#x20AC;&#x2122; diagnoses; decision making about clinical utility of testing or screening; and discussion about management, surveillance, support, and treatment. A geneticist may see patients who have questions about patterns (collections of related features that do or do not fit with the family); family history (assessments of what is or is not significant); family planning (recurrence risk, whether or not a genetic condition can be prenatally diagnosed); birth de12 13

San Francisco Medicine November 2013

fects (any malformations, differences, dysmorphisms); genetic syndromes; neurologic problems (intellectual disabilities, hearing loss, unusual vision loss, motor delays, neurodegenerative conditions); growth abnormalities (too short or too tall for family, body asymmetries); endocrine or metabolic conditions; skeletal dysplasias; connective tissue disorders such as Marfan syndrome; familial aneurysms and dissections; familial cardiac conditions (hypertrophic cardiomyopathy, certain arrhythmias); cancer syndromes or chronic diseases; hematologic disorders; multiple miscarriages, premature ovarian failure, infertility, stillborn infant or early neonatal death, and prenatally diagnosed birth defects; and preconception counseling and carrier testing.

Here are a few examples of the types of cases the genetics clinic might see.

A thirty-five-year-old woman has a newly diagnosed

unilateral invasive breast cancer. She comes to the genetics visit and gives the family history that her mother and maternal aunt both had breast cancer in their thirties. BRCA1/2 genetic testing is offered to her to help in her decision as to whether or not she should have prophylactic contralateral mastectomy and oophorectomy. She tests positive for a pathogenic mutation of the BRCA1 gene, and she opts for prophylactic surgeries. At-risk and affected family members are recommended to also have genetic testing of the BRCA1 gene to look for the same mutation to determine whether they should have increased monitoring for breast and ovarian and other cancers.

Continued on page 14 . . . www.sfms.org

Genetics

Hereditary Breast Cancer Stopping It Before It Starts Pamela Lewis, MD Angelina Jolie did women a great favor when she went public with the fact that she carries the BRCA1 gene mutation. Her decision to have bilateral mastectomies started a dialogue among women of all ages. For those who have already undergone risk-reduction surgery, she has validated their choice. For those diagnosed but as yet undecided, she has reduced the fear factor. As the mother of a teenage daughter, I can attest that the media bombards young women with unrealistic images of how they should look. For Jolie to place her life and family above her looks sends a new message. Hereditary breast cancer accounts for only 5 to 10 percent of all breast cancers. The cancers are often early onset and may be bilateral. Most are attributable to mutations in the BRCA1 or BRCA2 genes, transmitted as an autosomal dominant gene. It is important to note that it can be transmitted through maternal or paternal lines and is usually characterized by two or more affected generations. If ovarian cancer is part of the pedigree, it increases the chances the woman will be a carrier.

Fortunately, breast cancer genetics have become mainstream in clinical practice. There are several online tools physicians can use to estimate the risk that their patient carries a mutation. One of the most popular is called the BRCAPRO. The test itself is offered by many oncologists and breast surgeons in the office setting, and it can now be done with a mouth swish rather than a blood draw. Even before Jolieâ&#x20AC;&#x2122;s announcement, women were asking to be tested, and numbers continue to increase. Most just want reassurance that they probably do not carry the gene. But many women far overestimate their risk, so physicians should stick to the guidelines recommended by the National Comprehensive Cancer Network to determine which patients should be tested. These include women with a personal history of breast cancer diagnosed at or before age forty, breast cancer diagnosed at or before age fifty in a woman of Ashkenazi ancestry, breast cancer at or under age fifty and one firstor second-degree relative with breast cancer under age fifty and/or ovarian cancer, breast cancer and two or more relatives on the same side of the family with breast and/or ovarian cancer, ovarian cancer at any age, relatives of individuals with known mutations. Be sure to first test the family member with the highest likelihood to carry the gene. Cancer risk estimates for BRCA1 and 2 mutations are www.sfms.org

controversial. Estimates based on the highly penetrant families used to find these genes are high. In studies of lower-risk cohorts, such as population-based studies, lifetime risks are lower. For this reason, the risk of breast cancer in BRCA1 carriers has been estimated from 36 to 87 percent, with an estimate of pooled data of 65 percent. Estimates of contralateral cancer are as high as 60 percent. Most of this risk is in the first decade after diagnosis. Risk of ovarian cancer in BRCA1 carriers is between 27 and 45 percent. They also have a significantly increased risk of fallopian tube cancer. A lifetime risk of breast cancer in BRCA2 carriers is between 45 and 84 percent. The risk of ovarian cancer is lower, at 10 to 20 percent. It is interesting to note that when a pedigree contains an early-onset breast cancer at under age thirtyfive, cancer risks are 20 percent higher. In contrast to sporadic breast cancers, those arising in BRCA1 carriers are frequently triple negative (negative for the estrogen and progesterone receptors, as well as the HER2). Women under age sixty diagnosed with a triple negative tumor should be tested and a careful family history takenâ&#x20AC;&#x201D;a relatively new criterion, so looking at patientâ&#x20AC;&#x2122;s prior pathology is critical. BRCA1 carriers with small node-negative cancers may have a higher risk of micrometastatic disease. They also derive a greater benefit from chemotherapy. Most women who meet criteria for testing opt to be tested. If found positive, their options are many and require extensive discussion. Many decisions about how to proceed are based on the age of the patient and whether she has finished childbearing. Breast cancer screening has become optimal with the use of digital mammography with tomosynthesis, MRI, and whole-breast ultrasound. This screening regimen, coupled with a biannual physical examination, should detect a very small invasive or in situ carcinoma. Screening should begin at age twenty-five, or ten years before the youngest age of diagnosis in the pedigree. Discussion should include the option of bilateral mastectomies with reconstruction, since surgery statistically reduces risk by 90 to 95 percent. Like Jolie, many women opt for surgery because they are anxious about close follow-up and reluctant to undergo chemoprevention with hormonal agents. The problem arises with the ovaries, because even with rigorous screening, late stage at diagnosis is common. Screening for ovarian cancer should include transvaginal ultrasound every six months, as well as CA-125 starting at age thirty, or ten years before the earliest age of first diagnosis. Risk-reduc-

Continued on the following page . . .

November 2013 San Francisco Medicine

Hereditary Breast Cancer Continued from the previous page . . . ing salpingo-oophorectomy should be seriously considered at age thirty-five to forty, or individualized based on the patient’s family history. The oophorectomy is also risk reducing for the development of future breast cancer. These are challenging times for women, because science has provided them with choices they have never had before. It is amazing that new technology has enabled them to avoid life-threatening disease before its onset. But Jolie’s case has shown that women want to be informed and are up to the task of deciding their own fates.

Dr. Pamela Lewis is the medical director of the Sister Diane Grassilli Center for Women’s Health at St. Mary’s Medical Center and a member of the SFMS. She specializes in surgical oncology of the breast and performs surgical operations for both benign and malignant tumors of the breast as well as follow-up for high-risk patients. Dr. Lewis also specializes in sentinel lymph node biopsy, lumpectomies, oncoplastic surgery, and skin- and nipple-sparing mastectomies. She works closely with plastic surgeons to perform immediate reconstruction when possible.

A Day in the Life of a Geneticist Continued from page 12 . . .

A thirty-year-old woman, at the time of her first preg-

nancy, noticed whooshing sounds in her right ear, along with decreased hearing in that ear. Audiology results confirm mild conductive hearing loss of the right ear. Her tinnitus worsens with occlusion of the jugular vein. At her HNS (head and neck surgery) visit, it is noted that in her right ear she has a pulsatile mass in the inferior posterior external auditory canal, adjacent to the TM, obstructing 30 percent of it. CT angiography of the head revealed a glomus jugulotympanicum paraganglioma with permeative/destructive changes of bone surrounding the right jugular foramen and invasion of the right internal jugular vein. Eventually she has stereotactic radiosurgery for the tumor and has residual, mild right-sided hearing loss. For her second pregnancy, she requests a genetics consult due to concerns about radiation prior to her second pregnancy. During that visit, the option of genetic testing is offered because of her history of a single paraganglioma (jugulotympanic tumor), to determine if the tumor is related to hereditary paragangliomapheochromocytoma syndrome (http://www.ncbi.nlm.nih. gov/books/NBK1548/). She is recommended to first have sequencing of the SDHD (mitochondrial succinate dehydrogenase [ubiquinone] cytochrome b small subunit) gene, as mutations in this gene are most often associated with a jugolotympanic paraganglioma. She is found to have a commonly described mutation of the SDHD gene. Identification of the involved gene for this woman proved to be very important, because mutations in the SDHD gene are inherited in an autosomal dominant condition, and other family members (father and siblings) are at risk to also have this mutation. In addition, knowledge from other affected patients with a mutation in this gene can give some information prognostically. Genetic counseling about her recurrence risk is reassuring; mutations in SDHD are almost always paternally inherited due to imprinting. Surveillance guidelines are important to discuss: During pregnancy it is recommended that she have a twenty-four-hour urine collection to determine fractionated metanephrine and catecholamine levels to be sure she does not have a secreting pheochromocytoma, and screening for pheochromocytomas (imaging and biochemical testing) for at-risk family members should begin at age ten years or at least ten years before the earliest age at diagnosis in the family.

San Francisco Medicine November 2013

Targeted genetic testing for the SDHD mutation should be offered to at-risk family members.

A thirty-five-year-old pregnant woman decides to have NIPT (noninvasive prenatal testing), which is a blood genetic test of fetal cells in maternal circulation, at eight weeks of pregnancy. She is found to be at high risk (more than 1 in 10) to have a baby with Down syndrome. She elects to continue the pregnancy, and the diagnosis of Down syndrome is confirmed by CVS. She has a prenatal visit in genetics to discuss management, recommendations, resources, and support for families who have a child with Down syndrome.

A three-month-old male is noted by his pediatrician to

have body asymmetry, with the right side of his face, arm, and leg visibly larger than the left. He is referred to genetics for his hemihyperplasia. At the genetics visit, his diagnosis of hemihyperplasia is confirmed by physical exam, and recommendations for screening for embryonal tumors (Wilm’s tumor and hepatoblastoma) are initiated.

Primary care providers and specialists in other fields outside of genetics are encouraged to collaborate with geneticists. A patient should be evaluated as one part of an extended family. For each diagnosis, it is important to decide if it happened by chance, by genetic predisposition, or as a consequence of lifestyle or environment. As we head further into the era of genomics, and exome and whole-genome sequencing become more available and less expensive, we all have to work together to determine what genetic information will help us provide the most accurate, comprehensive, and best care for our patients. For more information about the role of genetics and genomics in health, see www.geneticsinprimarycare.org, www.genesinlife.org, www.acmg.net. Emily Chen, MD, PhD, is a clinical geneticist at Kaiser Permanente San Francisco and codirector of the Regional Molecular Genetics Laboratory at Kaiser Permanente San Jose. She is also a clinical professor at UCSF in the Department of Pediatrics, Division of Genetics. She is also a member of the SFMS. www.sfms.org

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Genetics

Everyday Epigenetics From Molecular Intervention to Public Health and Lifestyle Medicine Martha R. Herbert, MD, PhD Epigenetics, which refers to changes in which genes are turned on or off, rather than to the genetic

code itself, helps us understand that we have much more power over our health and well-being than we could have imagined when everything was thought to be determined by our genes. Although it is possible to design drugs to impact genetics, the path to truly proving safety and efficacy is long. Meanwhile, right now we can change our epigenetics through everyday choices such as eating high-nutrient-density food; avoiding junk food, allergens, toxicants, and infections; getting plenty of exercise and sleep; minimizing stress; and nurturing each other better. These evolutionarily tried-and-true approaches have documented impacts on epigenetics. They can help us avoid disease, reduce disease severity, and promote recovery. The serious chronic illnesses such as obesity, diabetes, autism, and cancer can all be impacted greatly by addressing epigenetics through presently available everyday changes. Public health and economics as well as each person’s desire for the best possible life all dictate that we promote these affordable and practical everyday epigenetic interventions. We are moving from the age of genes into the era of epigenetics. This means that we are recognizing that even with the same set of genes—the same set of genetic coding—there are many different options for how things turn out, because there are many ways that influence how genetic code is expressed, spliced, or not expressed. Now more than ever we know it is not solely our genes that determine our bodies, brains, and health—many other factors contribute as well.

Background

The emergence of epigenetics is opening up remarkable new avenues of investigation and insight into disease mechanisms. It is giving us more ways to articulate the specific ways that genes and environment might interact to influence development and health. It is also opening the way to fresh ideas about health promotion. Indeed, we have come a long way from the not-so-longago days of the “central dogma” of genetics. This was the idea that there is a one-way street from DNA to RNA to protein. It was accompanied by the expectation that we would find the causes of disease in a small number of genes, each of high impact. Now we know that there are hundreds of mostly lowimpact genes involved in the major chronic illnesses, that there are many different ways of having even single-gene mutation disorders, and that we are dealing with networks where influence runs in many directions. The term epigenetics refers to alterations in gene expression—from embryo to fetus to infant, child, and adult—and 16 17

San Francisco Medicine November 2013

it also refers to which genes are turned on and which are turned off. Gene expression is different at different phases in development—differs from one tissue type or organism to another. But epigenetics is also modified in further ways, many of which are just being discovered or fleshed out. On this account, epigenetics does not at present have a standard definition, though several processes are prominently associated with it, including DNA methylation, histone modification, non-coding RNAs, and microRNAs. Another way that the same DNA code can result in different proteins is alternative splicing, which generates protein diversity by utilizing and omitting different parts of the genetic code in generating proteins; this was previously thought to impact a small percentage of the human genome but today is known to affect the vast bulk of it. It also turns out that non-coding DNA—DNA that does not code for protein, that some call “dark matter,” can code for non-coding RNA, which is also implicated in epigenetics; embarrassingly, non-coding DNA used to be presumptuously called “junk DNA,” as if it couldn’t possibly be doing anything if it weren’t coding for DNA—whereas in fact it increases hugely in evolution as organisms become more complex and is highly functional. Does epigenetics bring us closer to treatments that will really make a difference in autism? Actually, the answer is probably yes. But are these novel treatments? At the moment, the main thing about the near-at-hand treatments that can impact health and improve the lives of people with autism is not that they are novel but that we now have novel explanations for treatments that have been around for a long time. Many of these treatments are inexpensive and widely applicable. Therefore, in this commentary I would like to consider the newly appreciated epigenetic dimensions of some old standby interventions and lifestyle modifications. This leads to the critical translational and transformational question: Can this new scientific plausibility allow us to finally get funding and policy support for implementing them in a large-scale public health program? They are presently available and could make a large difference to huge numbers of people.

Epigenetics: When?

In epigenetic discourse in autism, there has been a great deal of emphasis on prenatal contributors to epigenetic change. Prenatal stress, infection during pregnancy, exposure to toxicants, electromagnetic frequencies, and prenatal nutrition—these are some of the main factors that may contribute to epigenetic alterations with consequences that may persist far into the lifespan. However, many kinds of postnatal exposures and expewww.sfms.org

riences may also shape the ways that epigenetic modifications occur. This is very important, because it means that our personal choices matter, and that opportunities still exist to significantly influence development even after the extremely vulnerable and malleable period of gestation is over.

Everyday Epigenetics

Here are some of the levels at which mundane, everyday experiences may influence epigenetics.

Diet. A wealth of literature links diet to epigenetics in the postnatal as well as prenatal and preconceptional periods. Macronutrients: An imbalance or poor quality of macronutrients can contribute to pressures that may alter epigenetics. Imbalances may include low-nutrient-density, lowquality, high-glycemic-index carbohydrates such as sugar and high-fructose corn syrup. It may also include an excess of transfats and an insufficiency of essential fatty acids as well as an overly high omega 6:omega 3 fatty acid ratio. Proteins may not contain an appropriate balance of essential amino acids, or there may be problems or interference with intestinal absorption of critical amino acids such as cysteine.1 Micronutrients: Deficiencies or insufficiencies of various critical micronutrients are common in ASDs, and many of these are associated with epigenetic change. For example, folate is quite involved in epigenetics,2 and, particularly in the setting of lack of prenatal vitamins or food fortification, can increase autism risk.3-5 Zinc, often low in ASDs,6 is necessary for many neurological and systemic processes; its insufficiency can lead to many problems including compromised immune function, problems with sound healing, faulty DNA damage repair, increased oxidative stress, and epigenetic regulation of neuronal cells. Vitamin D is also known to have epigenetic influences,7 with improvement when deficiencies are overcome. One-carbon metabolism: The establishment and maintenance of DNA methylation is critically supported by onecarbon metabolism, which can be impaired by mutations that are fairly common in the general population but more common in ASD and family members of individuals with ASD, as well as with various other chronic conditions.8 It can also be supported by the presence of adequate precursors in the diet such as usable forms of folate, or impaired by the lack thereof. Intermediary metabolites: Dietary substances can be converted into intermediary metabolites that can modulate HDAC (histone deacetylase) activity. These include shortchain fatty acids, seleno-alpha-keto acids, small molecule thiols, mercapturic acid metabolites, indoles, and polyphenols.9 Different types of food intake may impact HDAC, and hence epigenetids, in different ways. Allergens and other immune triggers. Impact of al-

lergens on epigenetics may be mediated by their pro-inflammatory impact, since inflammation has marked epigenetic consequences.10 Certain substances such as gluten may amplify vulnerability to allergens and other immune triggers by contributing to compromise of the integrity of the intestinal gut-blood barrier, thereby increasing quantity and persiswww.sfms.org

tence of exposure to potentially allergenic, pro-inflammatory, and incompletely digested exogenous peptides.11 Such exposures can also promote mast cell activation, which can also compromise the blood-brain barrier.12 This cascade of proinflammatory changes and tissue compromise has great potential for contributing to maladaptive epigenetic change.

Noxious exposures. Toxicants, electromagnetic fields, and radiofrequency radiation (EMF/RFR) may alter epigenetics (as well as exert frank genotoxic damage to coding and noncoding DNA13). A particularly epigenetically relevant pathway of influence is through inhibition of methylation pathways and inhibition of the synthesis of glutathione.14,15

Inadequate or aberrant microbiome. Emerging research is showing both inadequate levels of normal components of the intestinal microbiome and aberrant organisms in ASDs.16,17 The microbiome is shaped by perinatal exposure to either vaginal or delivery room flora as well as to antibiotics should this transpire. It is also heavily nutritionally conditioned from early infancy.18 It plays important roles both in production of epigenetically active intermediary metabolites and in immune modulation.18 The impact of its products on the function of the brain is increasingly being elucidated19 and these mechanisms may turn out to include epigenetic components. Sleep. Sleep is a reparative, restorative process, but it is often compromised in ASDs. Disordered sleep can be both cause and consequence of inflammation, which, as mentioned, can impact epigenetics. Melatonin, a substance important to sleep, is commonly compromised in ASDs.20 Melatonin has epigenetic impacts21,22 and is also important in mitigating mitochondrial dysfunction,23 which is common in autism spectrum disorders.24 Mitochondrial bioenergenetics provide an important interface between the environment and the epigenome, with an increasing number of epigenetic diseases being associated with mitochondrial dysfunction.25 Stress and nurture. Some studies have associated stress

during pregnancy with increased risk for autism spectrum disorders,26,27 though others have not.28 Among the many mechanisms that could mediate this are impacts on steroid metabolism29 and impacts on oxidative stress. Stress and the quality of co-regulation of infant and caregiver are also shown to have epigenetic impacts.30,31 A sick, colicky child may elicit less effective nurturance from its mother or caregiver due to its chronic, exhausting, intractable discomfort that is not responsive to normal measures available to the mother. This could potentially have negative impacts on both the ability of the mother to nurture and the ability of the child to experience being nurtured, with consequent impacts on epigenetics.

Exercise and activity. Many children with ASDs spend their days in cubbies getting behavioral therapy, which may involve frequent use of low-nutrient-density, high-glycemicindex food reinforcers, in combination with very little exercise. This, in further combination with atypical antipsychotContinued on the following page . . .

November 2013 San Francisco Medicine

Everyday Epigenetics Continued from the previous page . . . ics often associated with marked weight gain and hormonal dysregulation, may produce a situation of obesity, prediabetes, and inflammation, which is most likely associated with epigenetic changes that increase risk of chronic illness and suboptimal brain function. Institution of a regular exercise regimen may reverse many of the adverse epigenetic impacts of this situation and reduce risk of metabolic dysregulation. Physical exercise is well known to have positive epigenetic impacts both in the brain, through improved hippocampal function and increased BDNF, and systemically, through damping down of inflammatory pathways. BDNF, in turn, is very important for neuronal development and plasticity.32

What’s on the Horizon for Targeted Epigenetic Interventions?

Drugs intervening in epigenetic processes could theoretically involve preemption of molecular or cellular abnormalities before they arise, or reversal of emerging or established abnormalities.33 However, while at present there is a range of pharmaceutical agents that aim at epigenetically relevant targets, these substances impact a wide range of pathways, and we have hardly begun to evaluate their safety and efficacy. Moreover, such evaluation will be complicated and protracted due to intrinsic concerns with slow-to-emerge long-term consequences, particularly if the treatments are used early in development. Thus, at this point in time we do not have drugs that allow us to target specific epigenetic processes safely and effectively. It may become possible to do this pharmaceutically in the future, but the model of targeting specific epigenetic processes for therapeutic processes remains fraught with risks of unintended additional effects that may cause adverse effects that could be profound. Meanwhile, environmental modulation through presently available lifestyle modification involves evolutionarily tried-and-true approaches that can significantly shift the baseline for large numbers of people and remove obstacles that interfere unnecessarily with treatment and progress for affected individuals. Promoting more constructive cellular processes through lifestyle modification such as improving diet, getting plenty of exercise and sleep, and avoiding toxins may be a safer approach to impacting epigenetics than molecular targeting. Moreover, given the underlying nutritional, metabolic, microbiome, and immune imbalances that are more and more abundantly being documented in ASDs, we need to be concerned that as people with ASD grow older they may face a markedly increased risk of chronic diseases such as cancer, obesity, diabetes, chronic immune conditions, and neurodegenerative diseases. It is no coincidence that the same basic lifestyle modifications discussed above in relation to ASDs are being shown to have preventive power in relation to these other chronic illnesses. A deeper issue that deserves mention is that the very idea that treatments aimed at specific targets are superior to treatments that have broader impact may be challenged by the 18 19

San Francisco Medicine November 2013

power of everyday epigenetics. For example, the transplantation into Rett syndrome mice of wild-type microglial cells without the MECP2 mutation restored health and neurological function to these mice without targeting specific synaptic deficits.34,35

Public Health and Lifestyle Epigenetics Can Be Implemented Now

At present, we already know enough to improve the everyday epigenetics of vast numbers of people. The problem here is not scientific but economic and political. While targeted epigenetic treatments may emerge in the future, and while some of them may turn out to be benign, we do not have to sit on our hands doing nothing while we wait for these clinical trials to proceed (and often fail). For myriad reasons, a concerted attempt to improve the baseline everyday epigenetics of the general population, and particularly the at-risk populations, is a path that we need to take as soon as possible to reduce the comorbidity patterns and suffering we are facing in autism spectrum disorder, as well as in many other severe health conditions such as diabetes and obesity, where very similar considerations apply. The political and economic programs are spelled out provocatively in a New England Journal of Medicine guest editorial in the fall of 2012 entitled, “What’s Preventing Us from Preventing Type II Diabetes?”36 where it is shown that we know how to prevent a large proportion of the illness on which we are spending $750 billion per year in the U.S.—it would basically require lifestyle coaching in diet and exercise—and yet we do not do it. It may well take a grass roots epigenetics/lifestyle medicine revolution to shake off the worsening health trends we are facing in the setting of a progressively sicker and more endangered planet. In order to improve our diet; reduce toxins, allergens, and infection; reduce stress and increase exercise and sleep; and better nurture each other, we not only need to make healthy personal choices but to aggregate these to make healthier social and planetary choices. Let everyday epigenetics inform science of what is possible so that we can respond on an appropriate scale to the magnitude of the crisis we are facing. Dr. Martha Herbert is author of The Autism Revolution: Whole-Body Strategies for Making Life All It Can Be (Harvard Health Publications/Random House, 2012), a neurologist and neuroscientist at the Massachusetts General Hospital/Harvard Medical School, and author of many publications and blogs available at www.marthaherbert.org, www.AutismRevolution.org, ww.autismWHYandHOW.org, and www.transcendresearch.org. References available at http://najms.net/wp-content/ uploads/v06i03p167.pdf. Reprinted from the North American Journal of Medicine and Science, July 2013, Volume 6, No. 3. www.sfms.org

Genetics

Pharmacogenomic Testing Are You or Your Patients Ready? Alan H. B. Wu, PhD Randy Jones, a Caucasian gay male, has casual unprotected sex with another male who is positive for the human immunodeficiency virus (HIV) but does not disclose this fact to Randy. A few weeks after this encounter, Randy complains of fever, swollen glands, and sore throat and sees his primary care physician. Because of the clinical presentation, his physician orders an HIV test. Both the rapid screening test and Western blot confirmatory assay are positive for the virus. After consideration of various HIV treatment options, Randy initiates a regimen that includes the antiretroviral drug abacavir. When Randy develops a mild rash, his doctor changes his HIV treatment to a combination that does not include abacavir and the rash resolves. However, additional intolerances to various antiretroviral medications lead the physician to rechallenge Randy with a regimen that contains abacavir. Within ten days, Randy develops a systemic rash that covers 40 percent of his body. His health quickly declines with hypotension, leukopenia, kidney failure, and liver injury, and he requires hospitalization. Randy dies a few days later. What do we know about delayed hypersensitivity, and, more important, could this tragedy have been prevented? For more than four years, the San Francisco General Hospital (SFGH) Clinical Laboratory has offered testing for human lymphocyte antigen (HLA)-B*5701, a pharmacogenomics marker associated with the development of abacavir-hypersensitivity reaction that is present in 5 to 7 percent of the general population. DNA is extracted from leukocytes, specific genes are amplified by polymerase chain reaction, and they are then tested for the presence of specific genetic variances. I was first contacted by Brad Hare, MD, of SFGH’s Ward 86 about abacavir-induced hypersensitivity reactions back in 2007. This was in conjunction with a visit by Dr. Simon Mallal of the Royal Perth Hospital and Murdoch University. He and his colleagues were completing the PREDICT trial, in which they showed that screening for the presence of the HLA-B*5701 allele and avoiding abacavir use among those who tested positive completely eliminated immunologically confirmed hypersensitivity reactions (100 percent negative predictive value) (NEJM 2008; 358(6):568-79). Today, all HIV-positive patients seen at SFGH who are being considered for abacavir therapy are tested for the presence of this variant (this genetic variance is not observed among Asians). Since instituting routine screening for HLA-B*5701 at SFGH in 2009, there have been no cases of hypersensitivity reaction to abacavir seen in the HIV clinic at SFGH. FDA clearance has been granted for the combination of abacavir and lamivudine with dolutegravir, an integrase inhibitor used to treat HIV patients. Dr. Hare believes this single pill will be popular and pharmacogenomics testing will be required www.sfms.org

for these patients prior to dosing. Pharmacogenomic testing for HLA-B*5701 is part of UCSF’s more global effort for personalized medicine.

Providing the right drug for the right patient at the right dosage and time is important for maximizing therapeutic efficacy and minimizing toxicity. It is false and dangerous to assume that all patients will react to medications in exactly the same manner. The indication for a particular drug and its recommended dosages are established by the pharmaceutical industry and regulated by the U.S. Food and Drug Administration to be applicable for the “normal” individual. However, genetic variances such as what was seen in Randy Jones can result in catastrophic outcomes. The FDA’s Center for Drug Education and Research (CDER) has scoured the world’s literature for research and clinical studies that link genetic associations to poor response or development of side effects. The CDER then made a bold step by requiring the relabeling of certain medications recommending pharmacogenomics testing prior to drug initiation. These actions were made in hopes of reducing adverse events and improving clinical outcomes. Among the drugs relabeled include irinotecan (gene: UDP-glucuronyltransferase), warfarin (cytochrome P450 2C9 and vitamin K receptor complex), azathioprine (thiopurine methyltransferase), carbamazepine and phenytoin (HLA-B*1502), allopurinol (HLA-B*5801), and the above-mentioned abacavir. The UCSF lab also tests for genetic variances within the gene for interleukin (IL)-28B, useful in predicting outcomes for hepatitis C patients treated with ribavirin and pegylated interferon. The FDA and CDER have also issued “black box” warnings to physicians regarding important genetic associations of cytochrome P450 2C19 and 2D6 for clopidogrel following stent placement for patients with cardiovascular disease, and codeine for children and breast feeding mothers, respectively. The UCSF Clinical Pharmacogenomics Laboratory in the Department of Laboratory Medicine offers testing for genetic variances for most of these drugs listed by CDER. There is an important gap in the knowledge of practicing physicians and the new clinical science of pharmacogenomics. UCSF has begun educating the next generation of physicians, pharmacists, geneticists, and laboratory medicine specialists. In the spring of 2013 in the Genetics and Pharmacogenetics Course given to first-year pharmacy students, course directors and faculty offered pharmacogenetic testing for one gene,

Continued on the following page . . .

November 2013 San Francisco Medicine

Pharmacogenomic Testing Continued from the previous page . . . cytochrome P450 2C19, to any student who signed a consent form and was willing to have blood taken. These students also agreed to have their DNA tested for pharmacogenomics variances. The relevance of these variances to drugs that are affected by CYP 2C19 was discussed in class with full disclosure of the student’s identity. Prior to this offer of participation, it was stressed to the students that there is no social stigma to genetic variances in the genes that control hepatic liver enzymes. Furthermore, pharmacogenomics variances are not linked to genetic predisposition to any disease. Consent and blood was obtained from twenty-two students. The lessons taught during this lecture were memorable, especially for those who were genotyped. Instead of providing basic pharmacology knowledge, we provided medical information that can affect how they themselves will behave should certain medications be needed for them in the future. Some students have commented that this genetic knowledge was helpful in explaining outcomes to those who were taking medications that are metabolized by hepatic 2C19. It can be presumed that family members can have similar genotypes to the students. Are we as a medical profession ready for pharmacogenomics testing? A deterrent for widespread limitation is the cost, which is 10- to 50-fold higher than for the common clinical laboratory tests. Moreover, pharmacogenomics testing is designed to detect outliers, i.e., those with an atypical genetic profile. Therefore the costs for detecting the occasional variant

must be amortized against the testing of individuals who are wild type and for whom a poor outcome is not expected. For example, if the test cost is $50 and the frequency of the rare allele is 1 percent, the cost of identifying that one individual is $5,000. As health care providers, can we justify these cases? The avoidance of abacavir would have saved the medical expenses and ultimately the life of our patient, Randy Jones. In this scenario, the benefit greatly outweighed the expense. Perhaps a rearrangement of a quote from a popular movie explains this situation best. In second of the original-cast Star Trek movies, The Wrath of Khan, a dying Spock says to Captain Kirk, “The needs of the many outweigh the needs of the few.” However, when it comes to pharmacogenomic testing, it is, “The needs of the few outweigh the needs of the many.” Alan H. B. Wu, PhD, is professor of Laboratory Medicine and adjunct professor of Clinical Pharmacy at the University of California, San Francisco, and is chief of Clinical Chemistry and Toxicology Laboratories at San Francisco General Hospital and chief of Clinical Pharmacogenomics at SFGH. He is also a member of the Graduate School of Pharmaceutical Sciences and Pharmacogenomics. Dr. Wu has ongoing clinical pharmacogenomics research projects in abacavir, clopidogrel, tamoxifen, warfarin, bosentan, and the statin drugs. This case presentation is fictitious and does not violate any privacy laws.

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Genetics

Commercialized Genomics Caveat Emptor Steve Heilig, MPH My dog is a mutt—part Australian shepherd, maybe mixed with some kind of retriever, Bernese mountain dog, who knows. I don’t much care and he certainly doesn’t. I could learn about his genetic heritage; for years now, companies have been offering, for a fee, to examine any dog’s spit and tell you that, yes—that’s a dog. This has always struck me as a pointless exercise; again, he’s a mutt, as am I. On the human side, most anytime I turn on my computer these days, various ads from outfits (like, say, 23andMe) pop up and offer to help anybody “learn about your ancestry” and “better manage your health” and more—if I send in some of my spit and, of course, money. “Find out things like if your body metabolizes caffeine quickly, or if you’re at a higher risk for diabetes. The more you know about your DNA, the more you know about yourself” says their homepage—a tautological statement that begs the real question: What might one really do with the knowledge? Not to pick on 23andMe—they are just the most visible “personal genomics” company so far, but: A lot of knowledgeable people are of the opinion that such testing isn’t of much practical use. Make no mistake, genetics can be important and there are many cases, particularly in reproductive medicine, where knowing more about the genetic makeup of oneself can be helpful. The BRCA issue in breast cancer is one visible example, other authors in this edition of San Francisco Medicine detail other useful, targeted diagnostic and treatment options. There are also some fascinating “big data”-type efforts underway, including at UCSF and Kaiser, to tease out risks linked to genetics. At this point, though, such research is in the “potential/future” state with respect to workable new interventions. A few years ago, San Francisco writer David Ewing Duncan explored within his body, including his genes, to write a book titled Experimental Man: What One Man’s Body Reveals About His Future, Your Health, and Our Toxic World. In it he revealed much about both the promise and the limits of the kind of personalized testing increasingly being hawked online and elsewhere. Duncan donated his blood for testing to examine his genes, brain, and body to “humanize science by having a real person with a family and children intimately participate in leading-edge technologies.” He aimed to provide some insight into a coming “new era of medicine” wherein we might “acquire profound new powers of knowledge about ourselves, possibly more than we want to know.” Duncan lost his “genetic virginity” mostly so that scientists might tell him of his probability of developing various diseases. He had far more testing than any of the “personal genetics” companies offer. In a blog post subsequent to his book, he warned that “Scientists don’t yet know what all our DNA does—how each difference in genetic code might influence disease or the www.sfms.org

color of your hair. Nor have studies confirmed that all the genetic markers linked to, say, heart disease and most cancers actually increase a person’s risk for these illnesses. Just as significant, the thousands of genomes being cranked out right now can’t easily be compared. There is no standard format for storing DNA data and no consistent way to analyze or present it.” Thus he received often-conflicting interpretations of his test results from various experts. Almost without exception, physicians he consults about his “DNA tower of Babel” use terms like “tentative” or even “irrelevant.” They do offer well-established advice we should already know—exercise more, don’t be overweight, don’t smoke, drink alcohol moderately, eat healthily, beware of high blood pressure, and so on. You don’t need any genetic tests to know these are good ideas, or to start practicing them. But these proven “interventions” don’t profit technology companies. A Harvard geneticist in Duncan’s book calls the new genetic testing “technology hucksterism.” But even if these tests become truly predictive, Duncan asks, “Who will have the time to analyze the data and to indulge the healthy in possible scenarios of future illness?” That’s a good question, and for the near future, the answer is still likely something like, “Mostly relatively affluent, gullible, perhaps even narcissistic hypochondriacs—and health insurers looking for new ways to exclude ‘risky’ patients.” This is a new example of the “technological imperative”—because something can be done, it should be done—and as we are learning all the time, that is not always a good thing in medicine, for multiple reasons. In the trenches, clinicians are increasingly besieged by the “worried well,” who bring all manner of marginally relevant information into exam rooms—at the “opportunity cost” of using valuable time addressing real health issues one might do something about. Policies are being put into place requiring that such tests, to be useful and covered, must be ordered by genetic counselors and knowledgeable physicians. Thus, for the foreseeable future, the wisest approach to these experimental tests might be nothing new, and of an entirely nontechnological type: Let the buyer beware. Steve Heilig, MPH, works on public health issues at the SFMS. He is also editor of the Cambridge Quarterly of Health Care Ethics. November 2013 San Francisco Medicine

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Public Health Update Joe Engelman, MD, MPH, and Stephanie Cohen, MD, MPH

Syphilis in San Francisco, 2000 to 2013 Infectious syphilis reached a historic low in San Francisco in 1999, with only 44 cases of early syphilis (primary, secondary, and early latent) reported. But starting in 2000, rates of early syphilis in San Francisco and other major metropolitan areas across the United States have climbed, with an epidemic resurgence among men who have sex with men (MSM). In 2012, there were 890 cases of early syphilis in San Francisco with the vast majority diagnosed in MSM. Approximately two-thirds of patients with early syphilis in San Francisco are HIV positive, almost a third have had syphilis diagnosed previously, and the median age is 40.

Clinical Presentation and Management Issues

Primary syphilis classically presents with a painless chancre at the initial site of exposure roughly four weeks after exposure. HIV-positive individuals may present with multiple chancres. Chancres of the oral cavity or anorectal region are common and again may be multiple. Chancres on digits or nipples can occur. Secondary syphilis should be considered in any male who presents with a generalized body rash, even if the palms and soles are spared. Scrotal involvement is common. Other findings of secondary syphilis that may be present are mucous patches in the oral cavity and mucosal surface of the prepuce and glans, as well as condyloma lata (moist, warty lesions in the anogenital region). Anal condyloma lata can mimic typical anal warts (caused by human papillomavirus), and a syphilis serology is indicated in any man presenting with new onset anal warts. Nontreponemal serologic tests for syphilis (RPR and VDRL) may not become reactive for a week after the development of a chancre. The treponema pallidum particle agglutination assay (TPPA), a treponemalspecific test, is more sensitive than the VDRL or RPR in primary syphilis. It is therefore important to order a TPPA, in addition to an RPR or VDRL, when evaluating a genital or anal ulcer. Dark field microscopy remains the diagnostic test of choice in primary syphilis but is not widely available. San Francisco City Clinic, the municipal STD clinic in San Francisco, performs dark field microscopy. Clients are seen on a drop-in basis, and we encourage providers to refer clients to City Clinic for evaluation of anogenital lesions. The RPR and VDRL are highly sensitive in secondary and early latent syphilis. False-negative RPR or VDRLs are rare in secondary or early latent syphilis but can occur in the setting of a very high titer (the “prozone” phenomenon). The treatment of choice for early syphilis is benzathine penicillin G 2.4 million units IM one time. Doxycyline 100 mg PO BID for fourteen days is the alternative treatment for patients with early syphilis who have a true penicillin allergy. If you suspect early syphilis but think the patient is unlikely to follow up, consider treating immediately after obtaining blood for serologic testing. By treating suspicious lesions aggressively, clinicians can render patients noninfectious and promote rapid healing of the lesions, thereby decreasing the risk of syphilis transmission. We recommend obtaining a VDRL or RPR titer on the day of treatment because this establishes a baseline for monitoring treatment response, and titers can vary considerably, even over the course of a few days. It is important to caution patients that they may experience a Jarisch-Herxheimer reaction, a self-limited, systemic reaction characterized by headache, fever, and myalgias that can occur between two and twenty-four hours post-syphilis treatment. www.sfms.org

All patients with newly diagnosed early syphilis should have a neurologic evaluation to assess for signs or symptoms of uveitis, hearing loss, or meningitis. If any symptoms or signs indicating eye, ear, or CNS involvement are present, lumbar puncture is indicated to rule out neurosyphilis. Consider consulting ophthalmology or infectious diseases in such cases. One week after treatment of uncomplicated primary or secondary syphilis, we recommend that the patient be reevaluated to assess for resolution of symptoms and findings. No serology is indicated at this return visit, but patients should be advised to have a repeat serology at three, six, nine, and twelve months after treatment to assess for a decline in titer. By following titers serially post-treatment, clinicians can assess for adequacy of treatment and screen for repeat infection, indicated by a sustained fourfold rise in titer after an appropriate decline. We suggest adding a syphilis serology to all routine HIV blood draws. All partners who have been exposed to cases of early syphilis within the past three months should be examined, tested, and treated with benzathine penicillin G or doxycycline. Even with a negative nontreponemal test, partners could be incubating syphilis and not have any visible signs of infection. Patients newly diagnosed with primary or secondary syphilis should be informed that a health worker from the health department will be contacting them to offer partner services.

Diagnostic or Management Questions

The Disease Prevention and Control Branch of the San Francisco Department of Public Health is here to support you in evaluating and managing patients with possible syphilis infection. For clinical questions, please call Joe Engelman, MD, at City Clinic at (415) 487-5595. For questions regarding a patient’s syphilis history (past treatment or syphilis test results), call Gloira Calero at (415) 487-5531. For more information, visit www.sfcityclinic.org.

San Francisco City Clinic Syphilis Pearls • Consider syphilis when evaluating a generalized body rash in a sexually active patient. • Order a TPPA (in addition to a VDRL or RPR) when working up a genital ulcer and consider referral to SF City Clinic for dark field microscopy. • Order an RPR or VDRL on the day of syphilis treatment, as this establishes a baseline for monitoring treatment response. • Consider syphilis (condyloma lata) when evaluating new anal warts. The treatment of choice for early syphilis for both HIV-positive and HIVnegative patients is benzathine penicillin G 2.4 million units IM x1. • Patients who report being a contact to a sex partner with syphilis should be empirically treated with penicillin, even if the RPR or VDRL is negative. • Any woman diagnosed with syphilis should have a stat pregnancy test performed. November 2013 San Francisco Medicine

MEDICAL COMMUNITY NEWS KAISER

SFVAMC

Robert Mithun, MD

Diana Nicoll, MD, PhD, MPA

Cancer genetics is a hot topic these days. In May of 2013, Angelina Jolie brought cancer genetics into the limelight when she publically shared her diagnosis of a BRCA mutation and her decision to have risk-reducing mastectomies. One month later, cancer genetics returned to the spotlight with a Supreme Court decision that bans gene patents, specifically addressing the patent held by Myriad Genetics on the two BRCA genes, BRCA1 and BRCA2. If you want to find out how all of this started, you can watch the fall 2013 release of Decoding Annie Parker, a movie that tells the story of the discovery of BRCA1, the first gene associated with inherited breast and ovarian cancer. All this attention to inherited breast and ovarian cancer has opened the floodgates for cancer genetic services in the clinic. Patients are more aware than ever about the possibility of hereditary cancer syndromes, and providers are identifying, and referring, more potentially at-risk patients. However, not all genetic referrals for high-risk cancer history lead to genetic testing, though they do lead to some type of recommendation. At Kaiser Permanente, we have been offering cancer genetic services for more than fifteen years and are ready for this new influx of referrals. We offer an introductory class to our members that provides an overview of the genetics of breast and ovarian cancer, including the dominant inheritance pattern, risks associated with gene mutations, and management options for mutation carriers. Our members can choose to attend class at a local facility or they can opt to watch an online version. We also provide an extensive family history review and genetic counseling for patients interested in genetic testing. Ultimately, the benefit of all the media attention is better care for patients who need it.

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Researchers at the San Francisco Veterans Affairs Medical Center have made advances in human genetics, both through population-based studies and direct studies of tissues samples. While the focus is on diseases that disproportionately affect veterans, the results have implications for the general population. Many skin cancers are caused by excess sun exposure, common in sunbathers and those engaged in desert warfare. Sarah Arron, MD, found that mutations in a protein responsible for normal growth are common in squamous cell carcinoma of the skin, the most important sun-linked cancer. Dan Bikle, MD, and Peter Elias, MD, identified genes linking vitamin D deficiency to sun- and chemical-induced skin cancers. Karla Kerlikowske, MD, showed that dense breast morphology is linked to cancer and identified genes associated with dense breasts, allowing better risk prediction. Chris Lau, PhD, who demonstrated how mutations in a Y-chromosome gene lead to testicular cancer, found similar mutations in other diseases with high male prevalence, such as liver cancer, Hirschsprung disease, and autism. Rajvir Dahiya, PhD, found mutations in prostate and kidney cancer tissue that predict cancer recurrence, suggesting the need for more aggressive treatment. Dolores Shoback, MD, identified genes causing parathyroid cancer and polyostotic bone disease with tumor formation. Michael Shlipak, MD, and Carmen Peralta, MD, identified genetic variants that predict kidney failure and albuminuria. Carl Grunfeld, MD, found a genetic variant that increases susceptibility of HIV-infected patients to heart disease. Mary Whooley, MD, who showed that depression contributes to heart disease, identified novel genetic variants associated with depression. The VA Million Veteran program is obtaining DNA samples from one million veterans for genetic analysis. The results will be added to VA’s electronic health record’s deidentified research database. This database will be the largest such research resource in the world and will eventually form the basis for a new era of personalized medicine.

San Francisco Medicine November 2013

UCSF Michael Gropper, MD

In the near future, new parents may go home from the hospital with not just a new baby but with something else—the complete sequence of their baby’s DNA. A new research program funded at $25 million over five years by the National Institutes of Health (NIH) will explore the promise—and ethical challenges—of sequencing every newborn’s genome. UCSF will receive $4.5 million from the NIH over the next five years for a pilot project to assess whether large-scale gene sequencing aimed at detecting disorders and conditions can and should become a routine part of newborn testing. The pilot is a core element of the emerging field of precision medicine, which aims to harness vast amounts of genetic and health data to create predictive, preventive, and precise care for patients. But with that opportunity come some concerns. Scientists know the damage caused by many mutations in our genetic code, but there are other mutations that come with unknown consequences. Would doctors be needlessly worrying parents to tell them their baby has a mutation of unknown significance? There are also mutations that don’t cause a disease by themselves but contribute to an increased risk of conditions ranging from heart disease to diabetes. What should doctors disclose about mutations that change the degree of risk, even if only slightly? Also, genetic findings in newborns have implications for that child’s entire family—but not all of them may wish to have this information. While newborn screenings reveal diseases that doctors can treat early, the genome also exposes illnesses that don’t strike until adulthood and lack any known treatment. Because of these concerns, it’s important to understand not only the technical aspects of gene sequencing in newborns and how they relate to patient care but also the ethical, legal, and social implications involved.

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CPMC Michael Rokeach, MD

Wishes for Wellness, CPMC Foundation’s biennial celebration and fund-raising gala, recently took place at the Fairmont Hotel. Dr. Martin Brotman, former CEO of CPMC and current senior vice president of Education, Research, and Philanthropy for Sutter Health, was this year’s honoree. The event highlighted CPMC Programs in Women’s and Children’s Health, Neurosciences, and Cancer and Integrative Medicine. Also saluted were physicians Laurie Green (OB/GYN), Mohammed Kashani-Sabet (Cancer), William Stewart (IHH), and David Tong (Stroke). Proceeds from the event will support a “wish list” of critical needs identified by CPMC and our physicians. CPMC’s Forbes Norris ALS Research and Treatment Center was profiled on a recent KGO-TV news segment. Amy Roman, augmentative communication specialist at the Forbes Center, was interviewed regarding a variety of new technologies that are being used to help ALS patients communicate with less difficulty. Roman believes the explosion of consumer products such as the iPad and Android tablets are ushering in a new era of lower-budget solutions, some of which are adapted on the fly by technicians at the center. For instance, laser pointer glasses allow patients to pick out words or letters from a fixed chart. The Forbes Center also runs a lending program with support from the ALS Association, matching patients with the most effective communication technologies, independent of cost. CPMC’s second annual Lung Cancer Symposium will take place on Saturday, December 7, 2013, at the Pacific Campus, Level A Conference Room. This half-day event will explore the indications for lung cancer screening and the importance of a multidisciplinary approach to screening detected abnormalities. Effective and alternative treatments for lung cancer will also be discussed. For more information, or to register for this event, please call Sirin Tgamol at (415) 641-6536. www.sfms.org

Brown & Toland Andrew Snyder, MD

While one can debate the finer points of the Affordable Care Act (ACA), passage of the act brought into the national discussion the concept of accountable care. Government ACO pilot programs such as Medicare’s Pioneer ACO project proved that our health care system can help improve the quality of care for complex, high-risk, high-cost patients while reducing costs. Brown & Toland Physicians was among the initial thirty-two health care organizations selected by the Centers for Medicare and Medicaid Services (CMS) to participate in the Pioneer ACO program, and our first-year results were very promising. As part of the Brown & Toland Pioneer ACO, approximately 190 physicians across the Bay Area provide care for more than 18,000 Medicare beneficiaries. Our Medicare ACO has generated $10.6 million in savings for CMS. The cost of care our physicians provided was six percent below Medicare’s estimate during the 2012 calendar year. The cost savings was generated by a number of factors, including the use of electronic health records and data analytics as well as care management services that include preventative services, disease management, transitions of care, at-home care, and compassionate care. Brown & Toland’s ability to deliver savings and improve the experiences of our most vulnerable patients was a good first step toward realizing better value and better care for the health care dollar. Ultimately, our industry will be measured by our ability to sustain these successes over larger and more diverse populations in the future.

Sutter Pacific Medical Foundation Bill Black, MD, PhD

Genetic screening is a high priority for many patients. With advances in technology, patients can be screened for dozens of genetic conditions at one time, with a blood test or a saliva sample. Genetic screenings give our patients more information about their health risks and risks for their babies or future offspring. At Sutter Pacific Medical Foundation, we are meeting increasing requests for these services with the leadership of Denise Main, MD, and Regina Arvon, MD, both maternal medicine specialists, board certified in medical genetics; and Eric Muller, MD, PhD, a board-certified medical geneticist and pediatrician. Under their combined guidance, genetic testing is done for all ages. Through our Prenatal Diagnosis Center, we offer a variety of tests for low- and high-risk pregnant women. Women and their partners can get integrated screening for Down syndrome and other conditions. A popular screening is the Counsyl Prenatal Panel, a screen for carrier status for more than eighty conditions, including cystic fibrosis, Tay-Sachs, and sickle cell disease. The screening can include fragile X syndrome, the most common inherited form of intellectual disability and autism. High-risk women are advised to meet with one of our board-certified genetic counselors to review family and personal history and choose diagnostic tests as desired. Diagnostic tests offered include chorionic villus sampling (CVS) and amniocentesis. “It’s a team approach,” Dr. Main said. “We also work with pediatric cardiologists and pediatric subspecialists. If we find a problem, we have the services to counsel the patient and maximize the patient’s safety.” Dr. Muller helps families and individuals, both children and adults, by providing a diagnosis to guide prognosis, recurrence risk, and, if available, specific treatment. Conditions he sees often include hearing loss, developmental delay/disability, regression, autism/autism spectrum disorders, failure to thrive, short stature, birth defects, heart defects, abnormal facial features, and epilepsy.

November 2013 San Francisco Medicine

IN MEMORIAM

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Herbert Asa Perkins, MD Herbert Asa Perkins, MD, passed away in July at the age of 94. Herb contributed profoundly to the fields of transfusion and transplantation medicine as well as to the education and training of scientists, fellows, physicians, and medical technologists. Born and raised in Boston of first-generation immigrants, Herb was an undergraduate at Harvard University. He completed medical school at Tufts University School of Medicine in Boston, during which time he courted and married the love of his life, Frances Perkins. He served active duty in the Southwest Pacific as a first lieutenant in the Army Medical Corps during World War II. Back in the U.S., he held teaching appointments at medical schools including Tufts, Stanford, U.C. San Francisco, and Washington University before settling in Palo Alto, where he and his wife raised five daughters. Herb’s work over the decades included solving bleeding problems in heart-lung bypass and open-heart surgeries, helping characterize the human leukocyte antigen (HLA) system and the role of HLA matching in organ and bone marrow transplantation, and preventing transfusion-transmission of HIV and other infections. He was director of research at Irwin Memorial Blood Bank (now Blood Centers of the Pacific) and ultimately served as its scientific director, medical director, president, and CEO. After retiring in 1993, he remained involved as a mentor at Irwin until the end of his life. Herb cofounded and served as director and chair of the board for the National Marrow Donor Program, was president of the American Society for Histocompatibility and Immunogenetics, chaired the Standards and Histocompatibility committees for the AABB, and was an associate editor for the Journal of Transfusion. He received AABB’s prestigious Fantas Award, recognizing lifetime contributions to the fields of transfusion medicine and cellular therapy, and is the namesake for a lectureship at the California Blood Bank Society Annual A Meeting. He was a longtime member of the SFMS.

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San Francisco Medicine November 2013

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at your dental plan It’s Open Enrollment time for the San Francisco Medical Society sponsored Group Dental program. This plan is designed to help you, your family and your employees minimize the out-of-pocket expense of regular dental care. This program helps you maximize your out-of-pocket savings by using network dentists, but also allows you to use any dentist you like and receive lower benefits. Following are many valuable benefits that can save you money: Annual Benefits of $2,000 per person for dental care, using network providers ($1,500 if you use non-network providers). During Open Enrollment only, members may join as an individual or as a group with your employees. Low, calendar year deductible of $50 per person ($100 per calendar year maximum for families). Pay no deductible on oral exams, x-rays and routine cleanings.

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