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When genomic info is linked to the EHR record

We can explore associations between genes and phenotypes

Genomic information plus clinical information in a large database allows us to identify genes associated with disease variants and truly begin precision medicine. In pharmacoepidemiology this will mean that we can identify patients who benefit most or are at greatest risk of an adverse event from a specific treatment.

The power of linking genomic information with clinical information is demonstrated in a recent study by Karnes et al 2017. They examined variations in major histocompatibility complex (MHC) and human leukocyte antigen (HLA) genes by linking information from DNA biobanks databases with EHR records for almost 30,000 people. Most importantly, they discovered previously unidentified associations between gene variation and disease severity for several conditions. They identified associations with type 1 diabetes and ankylosing spondylitis, among other conditions. Most importantly, they discovered several previously unidentified associations with MS and cervical cancer, as well as associations between gene variation and disease severity for several conditions.

The heatmap crosstabulates HLA alleles with a range of disease diagnoses with darker reds being stronger positive associations (the allele increases the probability of having the disease or phenotype) and darker blues being stronger negative associations (the allele is associated with a protective effect against the disease or phenotype).

The authors note that this is one of the first systematic studies of clinical phenotypes with HLA variation in a single population.

Genomics EHR database

Heatmap of four-digit HLA allelic associations with P < 1 × 10?5.

Data are publicly available www.phewascatalog.org

Drug Utilization Research: Methods and Applications

New Text – a Valuable Resource

The recently published text, Drug Utilization Research: Methods and Applications, represents a formidable accomplishment, pulling together a comprehensive range of information on all topics related to this key area. With 48 chapters, it addresses study design, data collection, secondary data sources, classification systems, measurement units, drug expenditures, statistical methods, data visualization, and much more. I was happy to see a chapter addressing issues around pediatric drug utilization, and chapters on drug utilization of pregnant women and older populations, as well.

From the publisher’s website:

Drug Utilization Research (DUR) is an eclectic scientific discipline, integrating descriptive and analytical methods for the quantification, understanding and evaluation of the processes of prescribing, dispensing and consumption of medicines and for the testing of interventions to enhance the quality of these processes. The discipline is closely related and linked mainly to the broader field of pharmacoepidemiology, but also to health outcomes research, pharmacovigilance and health economics.

Drug Utilization Research is a unique, practical guide to the assessment and evaluation of prescribing practices and to interventions to improve the use of medicines in populations. Edited by an international expert team from the International Society for Pharmacoepidemiology (ISPE), DUR is the only title to cover both the methodology and applications of drug utilization research and covers areas such as health policy, specific populations, therapeutics and adherence.

The only way to assemble such a book is with a strong group of editors, Monique Elseviers, Björn Wettermark, Anna Birna Almarsdóttir, Morten Andersen, Ria Benko, Marion Bennie, Irene Eriksson, Brian Godman, Janet Krska, Elisabetta Poluzzi, Katja Taxis, Vera Vlahovi?-Pal?evski, Robert Vander Stichele are all accomplished researchers in this field.

What, precisely, is the precision medicine initiative?

First of all, it’s a big deal, high on President Obama’s agenda and with its own page on the White House Web Site

Near term goals

One immediate goal of the Precision Medicine Initiative will be to significantly expand efforts in cancer genomics to create prevention and treatment successes for more cancers.

But the long term goals are broader

the Initiative will 1) support a national network of scientists who possess the talent and skills to develop new approaches for answering critical scientific and medical questions and 2) launch a national cohort study of a million or more Americans to propel our understanding of health and disease. The goal is to set the foundation for a new way of doing research that fosters open, responsible data sharing with the highest regard to patient privacy, and that puts engaged participants at the center.

Precision Medicine Initiative logo

You’ll soon recognize the PMI logo

Some specific research questions would be to:
  • Identify genomic variants that affect drug response
  • Assess clinical validity of genomic variants associated with disease
  • Identify biomarkers that are early indicators of disease
  • Understand chronic diseases and best management strategies
  • Understand genes/pathways/factors that protect from disease

In the process, we will learn about EHRs, mhealth, patient engagement and new research methodologies.

Transparency

Workshops conducted by the PMI Working Group are open to the public if space is available, and can be viewed on webcasts. The recent workshop on Participant Engagement and Health Equity (July 1 and 2, 2015) was phenomenal, and worthwhile catching the video.

The challenge of pediatric Patient Reported Outcomes (PROs)

Think about it. We want to know how the child experiences his or her illness and therapies, and we can just ask, right? Well, some children are too young to even understand or respond to questions, infants and young toddlers, others go through a “no” stage and answer “no” to every question, and others may be unable to respond to questions for a range of other reasons.

Pediatric patient reported outcomes (PROs)

The recent IOM workshop, Comprehensive Cancer Care for Children and their Families, touched on some key issues around use of PROs in children with cancer, and much of what was said is applicable to children with other diseases and conditions. I’m hoping that video of the presentations will be posted (they often are).

The research imperative to develop pediatric Patient Reported Outcomes (PROs)

Try presentation by Lillian Sung, The Hospital for Sick Children, Toronto has the bland title “Academic Perspective on Clinical Research”, but is a hard hitting overview of the issues around implementing Patient Reported Outcomes (PROs) in pediatric cancer patients, and includes a full list of action items and recommendations. She notes the FDA 2009 Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims and its statement,

We discourage proxy-reported outcome measures for this population (i.e., reports by someone who is not the patient responding as if that person were the patient). For patients who cannot respond for themselves (e.g., infant patients), we encourage observer reports that include only those events or behaviors that can be observed.

Pediatric Patient Reported Outcomes (PROs) to improve estimates of toxicity and adverse events

Bryce Reeve made a critical point in favor of use of PRO’s in pediatric cancers. He presented evidence that there is a low correlation between clinicians’ report and patient report for a range of symptoms. The consequence of relying on clinicians’ report for identifying adverse events is an underestimate of adverse events, something that can be corrected by broader use of PRO’s in cancer research. Presumably this is relevant to other diseases, as well.

Other resources

The current measles outbreak and the importance of vaccines

An unnecessary, completely avoidable outbreak of Measles in the United States.

First, the science.

Measles vaccination protects against measles.  The measles vaccine, and so many other vaccines, are some of the biggest successes in public health, leading to almost 100% decreases in the incidence of a wide range of fatal and disabling infectious disease.

Measles vaccinations

Measles cases in the United States, 1950-2001, CDC

 

Parental concerns

Some children have medical conditions that preclude vaccination (see CDC “Who Should Not Be Vaccinated”), but this is a small group. Some parents of healthy children believe (without any basis) that measles vaccines (and others) cause a range of negative health effects in children and, the current generation of parents born in the 1970’s, 80’s and 90’s, don’t remember how deadly infectious diseases can be. A third group of parents have religious beliefs opposed to vaccination.

The law

Most states require vaccinations before entry to the kingergarden, but may allow unvaccinated children to attend pre-school. Some states provide exemptions for religious or other objections (see the CDC database for state immunization laws).

 Current Measles vaccination behaviors

Because vaccinations have been so successful in eradication of infectious diseases, people have forgotten how terrifying and harmful the diseases were, and have focused their anxieties on the vaccines instead of the disease. This figure shows a downward trend in measles vaccine coverage in the United States, between 1980 and 2013, and the decline from initial high levels of 97 and 98% down to current levels of 91% is enough to affect herd immunity and allow the current outbreak of measles.

measles vaccinations

Measles vaccination rates in the US 1980-2013, WHO

 

The result – an unnecessary, completely avoidable outbreak of Measles in the United States

On the upside –

a vigorous discussion and flood of information reminding us all about the value of vaccines and the importance of vaccination, including a wide range of articles, stories and commentaries giving voice to the message.

Great overview in the The New York Times

Articles and cartoons in The New Yorker (not sure it is helpful to call people “idiots”), but an indication of the widespread involvement in the discussion.

http://www.newyorker.com/cartoons/daily-cartoon/daily-cartoon-monday-february-2nd-measles-disneyland

http://www.newyorker.com/humor/borowitz-report/zombie-jonas-salk-rises-grave-hunt-idiots

Roald Dahl’s account of his 7 year old daughter’s death from measles.

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