A Mad Hatter’s Question About Correlating Transcriptomics to Proteomics

A Mad Hatter’s Question About Correlating Transcriptomics to Proteomics

Why is a raven like a writing desk? Lewis Carroll penned this head-scratcher over a century ago in his book, Alice’s Adventures in Wonderland. Since then, people keep trying to draw parallels between these two unrelated items to answer the Mad Hatter’s baffling riddle. In Omicsland, a similar riddle could be uttered at a social gathering, “Why is transcriptomics (looking at the RNA levels in an individual) like proteomics (looking at the protein levels in an individual)?”

If logic based on biology’s central dogma (DNA begets RNA which begets protein) is applied, the initial response might be because they are equivalent with respect to tracking protein levels. If the level of mRNA (messenger RNA that codes for the protein) rises, then the amount of the corresponding protein would rise too. This logic is not entirely sound. It was shown that mRNA levels do not always correlate with protein levels (Vogel & Marcotte, 2012). Recently, additional research has poked holes into research saying that the two omics correlate well (Fortelny, Overall, Pavlidis, & Freue, 2017). I’ll briefly elaborate about this lack of correlation, but a more thorough explanation (Liu, Beyer, & Aebersold, 2016) bears a tag saying, “Read me.”

One mRNA does not beget just one protein. Many proteins can be created from the same mRNA. The efficiency of this process can be affected by several factors. One of the major influences can be found within some, but not all mRNAs themselves. The mRNA can possess chemical modifications that can affect the process of making protein (Zhao, Roundtree, & He, 2017), possess internal elements that serve as video game-like cheat codes to fast track the process (Walters & Thompson, 2016) or contain binding sites for proteins that help regulate when the mRNA should be used (Nelson, Leidal, & Smibert, 2004). Another major influence can be found in the regulation of proteins (besides the ribosome) that are involved in converting the mRNA code into a protein (Nho & Peterson, 2011).

Aside from biological reasons, technology issues can sometimes explain why mRNA levels do not correlate with protein levels. Variations in how a technique is executed and how data are analyzed abound, and can affect the results. Also, technical approaches have their limits and may not be the best ones to use for certain tasks (e.g., using flamingos as croquet mallets). Best practices and new approaches are being proposed to help address the limits and reduce the variation that can arise (Conesa et al., 2016; Hu, Noble, & Wolf-Yadlin, 2016).

As noted earlier, correlation between proteomics and transcriptomics is low. However, a small percentage of protein levels do correlate with mRNA levels. This correlation, however, may only happen in certain instances or biochemical pathways (Liu et al., 2016; Zhang et al., 2016).

Let’s revisit the original question, why is transcriptomics like proteomics? The answer could simply be that the two are alike because they are both complicated. Correlating the two is feasible, but not without peril. With a low correlation, is it worth jumping down the rabbit hole to draw parallels between the two?

Resources

Conesa, A., Madrigal, P., Tarazona, S., Gomez-Cabrero, D., Cervera, A., McPherson, A., . . . Mortazavi, A. (2016). A survey of best practices for RNA-seq data analysis. Genome Biol, 17, 13. doi:10.1186/s13059-016-0881-8

Fortelny, N., Overall, C. M., Pavlidis, P., & Freue, G. V. C. (2017). Can we predict protein from mRNA levels? Nature, 547(7664), E19-E20. doi:10.1038/nature22293

Hu, A., Noble, W. S., & Wolf-Yadlin, A. (2016). Technical advances in proteomics: new developments in data-independent acquisition. F1000Res, 5. doi:10.12688/f1000research.7042.1

Liu, Y., Beyer, A., & Aebersold, R. (2016). On the Dependency of Cellular Protein Levels on mRNA Abundance. Cell, 165(3), 535-550. doi:10.1016/j.cell.2016.03.014

Nelson, M. R., Leidal, A. M., & Smibert, C. A. (2004). Drosophila Cup is an eIF4E-binding protein that functions in Smaug-mediated translational repression. EMBO J, 23(1), 150-159. doi:10.1038/sj.emboj.7600026

Nho, R. S., & Peterson, M. (2011). Eukaryotic translation initiation factor 4E binding protein 1 (4EBP-1) function is suppressed by Src and protein phosphatase 2A (PP2A) on extracellular matrix. J Biol Chem, 286(37), 31953-31965. doi:10.1074/jbc.M111.222299

Vogel, C., & Marcotte, E. M. (2012). Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet, 13(4), 227-232. doi:10.1038/nrg3185

Walters, B., & Thompson, S. R. (2016). Cap-Independent Translational Control of Carcinogenesis. Front Oncol, 6, 128. doi:10.3389/fonc.2016.00128

Zhang, H., Liu, T., Zhang, Z., Payne, S. H., Zhang, B., McDermott, J. E., . . . Investigators, C. (2016). Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer. Cell, 166(3), 755-765. doi:10.1016/j.cell.2016.05.069

Zhao, B. S., Roundtree, I. A., & He, C. (2017). Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol, 18(1), 31-42. doi:10.1038/nrm.2016.132

Understanding the Ramifications of Mutations: Seeing Past the Trees to the Forest

Understanding the Ramifications of Mutations: Seeing Past the Trees to the Forest

Remember Jurassic Park?  I can. I still get shivers thinking about the dinosaurs crashing through the trees and devouring anything that moves. I also recall the adorable animation the park visitors watched to better understand how the dinosaurs were brought back from extinction via the DNA in their blood cells trapped in those ancient mosquitoes encased in amber. This introduction to genetic engineering via Hollywood initiated my scientific endeavor for learning more about nucleic acids. I was hooked.

Since then, I have joined the countless masses who have become enthralled with the double-helix. We believed that the message that dictated our uniqueness resided in that simple, repetitive molecule. Thanks to technological advances, reading these messages has become both easy and affordable. As a result, the scientific literature is inundated with genome wide association studies (GWAS), which search for genetic changes that are related to many different diseases and conditions (Manolio, 2017).

Boyle et al. raised the question as to whether or not they should limit their focus to just a small subset of genes identified from GWAS to better understand disease or inheritable traits (Boyle, Li, & Pritchard, 2017). In their recent Cell publication, the group of scientists concluded that while a “core” set of genes might be a cause for something, the overall phenotype (physical or observable characteristics) resulted from many small contributions from many more genes. The authors stated that while the initial impulse may be to do even more GWAS, a different approach may be needed. They recommended doing an omnigenics analysis of GWAS data.

What is “omnigenics” you may ask? For complex traits or diseases, any gene variant in the genome could be contributing to the manifestation of the disease or trait. Hence, to truly understand the genetic cause of a disease or trait, all DNA mutations need to be considered. Even if the mutation seems to affect a system seemingly unrelated to the disease or trait of interest, it should be included in the analysis.

Recently, a study was published that showed that individuals were carrying disease-causing gene variations, yet the carriers showed no physical manifestation of the disease (Chen et al., 2016). The reason could be what the Boyle et al. had suggested: The manifestation is dictated by the genomic forest and not by a few gene trees.

This omnigenics approach sounds lovely, but it comes with its own issues. How do we truly separate legitimate changes from the background to understand the causes of disease? If we look at the data, is it possible that we are just looking at a pile of sawdust trying to pretend to be the desired forest? With so much information embedded in DNA, it can be a daunting challenge to establish causality no matter how good the software that sifts through the info.

Instead of considering our DNA, maybe it would be worthwhile to change focus and look at the proteomic (all proteins that constitute our bodies) forest. Being the products of our genes, proteins offer a timelier view of what is happening in our bodies. Understanding how changes in the protein, such as concentration, correlate with disease or inheritable traits may shed more light onto how different biological systems interact with one another in the body. It could also help explain exactly how simple genetic change(s) in an unrelated pathway could affect a physical trait. This capability would certainly explain what happened in the Jurassic Park dinosaurs, which had frog DNA inserted into their genomes, to allow some of them to become male.

References

Boyle, E. A., Li, Y. I., & Pritchard, J. K. (2017). An Expanded View of Complex Traits: From Polygenic to Omnigenic. Cell, 169(7), 1177-1186. doi:10.1016/j.cell.2017.05.038

Chen, R., Shi, L., Hakenberg, J., Naughton, B., Sklar, P., Zhang, J., . . . Friend, S. H. (2016). Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nat Biotechnol, 34(5), 531-538. doi:10.1038/nbt.3514

Manolio, T. A. (2017). In Retrospect: A decade of shared genomic associations. Nature, 546(7658), 360-361. doi:10.1038/546360a

Cancer: The Ultimate Malware

A horrified astronaut utters over the radio, “Uh…Houston, we have a problem. Someone just hacked our computers. Now, we are viewing a message that states we must pay a ransom of 20,000 bitcoins or lose our top-20 karaoke playlist! Please advise.” I bet this conversation never occurred during lunar missions from the 60’s and 70’s.

Today, our beloved cell phones carry more computational capacity than the computers used to get men to the moon (NASA, 2017). As we become even more dependent on phones and other computers to help navigate our everyday lives, we become more vulnerable to malicious hackers or malware that can render them useless, or worse, steal valuable data.

Cancer, a biological equivalent to hackers and malware, can overtake our bodies and create such havoc that it disrupts our day-to-day lives or even ends them. As in the computer technology sector, large resources are being poured into figuring out how the hacks occur and how to remedy the situation. Recently in Nature, two articles were published detailing hacking methods used by some cancers that involve taking over how cells normally communicate with one another and control cell fate.

In a typical scenario, cells communicate with one another using proteins that decorate the outer surface of the cell or are excreted (Perrimon, Pitsouli, & Shilo, 2012). These proteins will bind to another protein (known as a receptor) found on the surface of another cell. This binding event triggers a cascade of internal events that can cause a cell to carry out a specific function, such as transforming into a different cell. Pending how the involved proteins have been modified (e.g., by sugars, phosphates or other chemical compounds added to the proteins), the resulting cascade can have very different outcomes. For instance, this type of cellular communication can tell an embryonic cell to become part of a hand, foot, heart, brain, etc.

When cancer hacks the system, normal cell fates are compromised. In lung adenocarcinoma for example, Tammela et al. found that the tumor cells can differentiate into two types (Tammela et al., 2017). One type is a typical tumor cell. The second cell type almost appears like a “normal” cell, but it is producing proteins that can fuel the cancer (think of adding gasoline to a raging fire). In another study, Lim et al. also saw how cancer cells can fuel their own fire (Lim et al., 2017). In small-cell lung cancer, neuroendocrine tumor cells, which produce hormones (messages to other cells) in response to signals received from the nervous system, switch to a different cell type upon activation of a pathway that can suppress tumor growth. These new cancer cells tend to be resistant to chemotherapy, and produce signals that encourage proliferation of the original neuroendocrine tumor cells. In these two studies, the authors suggest that these hacking strategies could be the source for new biomarkers or targets for new therapeutics.

As our understanding of this malicious hacker/malware improves, we can develop better diagnostics or patches (therapeutics) that can protect our most valuable asset, our health. How nice would it be to go to a doctor’s office, take a blood test and learn that we need the anticancer patch v2.0? This is already a reality for our phones and computers. Only time will tell if it becomes reality for the doctor office equivalent. If we can get a person to the moon with technology that fits (in most cases) in our back pocket, then maybe the time is getting closer?

References

Lim, J. S., Ibaseta, A., Fischer, M. M., Cancilla, B., O’Young, G., Cristea, S., . . . Sage, J. (2017). Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature, 545(7654), 360-364. doi:10.1038/nature22323

National Aeronautics and Space Administration (NASA). Do-It-Yourself Podcast: Rocket Evolution. Retrieved on June 17, 2017 at https://www.nasa.gov/audience/foreducators/diypodcast/rocket-evolution-index-diy.html

Perrimon, N., Pitsouli, C., & Shilo, B. Z. (2012). Signaling mechanisms controlling cell fate and embryonic patterning. Cold Spring Harb Perspect Biol, 4(8), a005975. doi:10.1101/cshperspect.a005975

Tammela, T., Sanchez-Rivera, F. J., Cetinbas, N. M., Wu, K., Joshi, N. S., Helenius, K., . . . Jacks, T. (2017). A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature, 545(7654), 355-359. doi:10.1038/nature22334

The Guiding Light: How Medical Insights Can Steer Us to Better Health

I love the map feature on my smart phone. I am no longer burdened by carrying a stack of maps that feel like they could fill every library in the world thrice over. And unlike print maps, the map program can tell me if I’m about to encounter bumper-to-bumper traffic or some other horrible event. It truly is a wonderful piece of technology. If only, we could have something similar when it comes to our health. Well, maybe we do.

The market is inundated with wearable devices and other pieces of technology that can help improve our healthcare. Using personal data and other bits of data, we can have a lovely voice, vibration, etc. tell us it’s time to move, what exercises to do or what foods to eat. Technology has even advanced to the point that wearables can deliver insulin (or another medication) when a patient needs it (Amgen, 2017; Falcone, 2015). These technological advancements have provided people wonderful new ways to manage their health.

What if, though, we could see deeper, casting light all the way to the molecular level? Would we get more insightful information? Evidence already suggests yes. Consider the emerging field of proteomics (measuring the constant changes in the proteins that constitute us). Proteins are the products encoded by our genomes and responsible for what happens in the cell. Changes in protein concentrations or combinations can be an early warning of an oncoming health event (Schubert, Rost, Collins, Rosenberger, & Aebersold, 2017). To measure thousands of proteins over a very broad concentration range simultaneously and quickly, however, proves to be a daunting challenge long recognized (Chandramouli & Qian, 2009).

SomaLogic, a company nestled in Boulder, CO, has discovered a way to achieve what may have seemed impossible. Instead of relying upon mass spectrometry (a conventional means of looking at proteins), SomaLogic has developed a unique, chemically-synthesized affinity agent (known as a SOMAmer) for each protein. At the moment, over 1,300 SOMAmers are available and more are in the works. SomaLogic incorporates the SOMAmers into a SOMAscan assay to detect changes in the proteome (over a very large concentration range).

The SOMAscan platform can provide insights that are invaluable to the medical community. For example, the information gleaned from the technology provided risk scores for an oncoming health event (such as a stroke or heart attack), which was better than conventional methods (Ganz et al., 2016). In another instance, the SOMAscan platform could retroactively identify patients who would suffer an adverse reaction to a drug being tested in clinical trials. The platform even identified the organ systems that would be affected by the new drug (in progress).

The power of the SOMAscan assay is being increasingly recognized by many different researchers in many different fields. In recognition of its potential, the Chinese “Digital Life” company iCarbonX invested $161 million dollars into SomaLogic to push protein-based health insight generation further and faster (Bonislawski, 2017). In the near future, the SOMAscan platform is going to expand from the currently offered 1,310 SOMAmers to more than 5,000. It is envisioned that a version of the SOMAscan platform will one day be able to identify and monitor the 20,000 proteins that constitute our bodies (Bonislawski, 2017). By coupling the technology with biological samples provided by collaborators/partners, the company intends to deliver deep insights that carry the potential of identifying oncoming medical events, grade a response to a medical treatment or lifestyle choice, and more.

With this type of molecular vision, it is possible that individuals will be empowered to take progressive action to enjoy greater health for most their lives. This may prove beneficial in other ways, such as decreasing medical care costs by catching things early and decreasing health insurance costs because people are staying healthier longer. I can hardly wait till my phone has a feature linked to this technology. I can already hear the lovely voice say, “Alert. A (insert a medical event of choice here) is in your near future. Time to change direction.”

References

Amgen (2017, April 18). Retrieved from https://www.amgen.com/media/news-releases/2017/04/amgen-launches-neulasta-pegfilgrastim-onpro-narratives/.

Bonislawski, A. (2017, May 25). With $161M In Funding, SomaLogic Shifting Focus to Dx and Wellness Products. Retrieved from https://www.genomeweb.com/proteomics-protein-research/161m-funding-somalogic-shifting-focus-dx-and-wellness-products

Chandramouli, K., & Qian, P. Y. (2009). Proteomics: challenges, techniques and possibilities to overcome biological sample complexity. Hum Genomics Proteomics, 2009. doi:10.4061/2009/239204

Falcone, A. (2015, October 13). Doctors and Patients See Benefits of Wearable Technology. Retrieved from http://wnpr.org/post/doctors-and-patients-see-benefits-wearable-technology/.

Ganz, P., Heidecker, B., Hveem, K., Jonasson, C., Kato, S., Segal, M. R., . . . Williams, S. A. (2016). Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients With Stable Coronary Heart Disease. JAMA, 315(23), 2532-2541. doi:10.1001/jama.2016.5951

Schubert, O. T., Rost, H. L., Collins, B. C., Rosenberger, G., & Aebersold, R. (2017). Quantitative proteomics: challenges and opportunities in basic and applied research. Nat Protoc, 12(7), 1289-1294. doi:10.1038/nprot.2017.040

Before It’s Too Late: Finding and Diagnosing Cancer Correctly

Beep. Beep. Beep. Shhhh. Whoosh. Beep. These noises fill the sterile cold hospice room. Benevolent Uncle Ted lies unconscious with a steady drip of pain relieving medicines entering his once muscular arms via an IV. Uncle Ted has prostate cancer that spread throughout his body. As the curtain slowly closes on young Uncle Ted’s life, one wonders, “If the cancer had been found sooner, would Uncle Ted be playing with his kids, sailing, hiking or enjoying a fine wine with friends and family right now?”

This sentiment is a commonly held belief. But what if screening yields many false positives and could cause more harm than good? Recently, the U.S. Preventive Services Task Force has recommended that people who are not at high risk forgo screening for thyroid cancer. It was found that in places where over diagnosis occurs, patients have undergone surgeries to remove growths found on the thyroid, but the overall number of thyroid cancer-related deaths remains unchanged. Also, the patients getting the growths removed were undergoing unnecessary treatment that carried the potential of causing more harm than good (Jin, 2017).

With prostate cancer, the same holds true. Out of 1000 men, 100 to 120 men may get a false-positive result, which leads to further testing and biopsies (National Cancer Institute, 2017a). The biopsy procedures are not without risk and the description of the procedures would cause most men to cringe (National Cancer Institute, 2017b). With all this prostate screening, only about 0.1% may have benefitted from the early screening (National Cancer Institute, 2017a). Maybe a more definitive test that does not require biopsies could be developed and save more lives?

International efforts are underway to probe easily acquired samples, such as blood and urine, to identify better biomarkers that could identify individuals with deadly prostate cancer. In these samples, researchers are targeting exosomes (small packages that originated from cells, such as prostate cancer cells, that are full of proteins that may be useful biomarkers). After optimizing a protocol for harvesting exosomes, one group identified several biomarker candidates from individuals with metastatic prostate cancer using the SOMAscan assay (Welton et al., 2016). Another group also used the SOMAscan assay to examine exosomes (originated from prostate cancer cell lines) and found biomarker candidates for prostate cancer (Webber et al., 2014). The biomarkers identified by both groups could one day be used to screen men to determine if they have the deadly prostate cancer. While the work is very encouraging, further evaluation is still needed.

With the SOMAscan assay yielding valuable insights into one’s health, the number of unnecessary risky (and cringe-worthy) medical procedures could go down. Also, people may learn of detrimental diseases earlier through the non-invasive testing. If Uncle Ted had the opportunity, he may have found himself in a different scenario at the closing of his life story.

References 

Jin, J. (2017). Screening for thyroid cancer. JAMA, 317(18), 1920. doi:10.1001/jama.2017.5254

National Cancer Institute (2017a). Benefits and Harms of PSA Screening for Prostate Cancer. Retrieved from https://www.cancer.gov/types/prostate/psa-fact-sheet.

National Cancer Institute (2017b). Prostate-Specific Antigen (PSA) Test. Retrieved from https://www.cancer.gov/types/prostate/psa-fact-sheet.

U.S. Preventive Services Task Force (2017). Final Evidence Review: Thyroid Cancer: Screening. Retrieved from https://www.uspreventiveservicestaskforce.org/Page/Document/final-evidence-review159/thyroid-cancer-screening1

Webber, J., Stone, T. C., Katilius, E., Smith, B. C., Gordon, B., Mason, M. D., . . . Clayton, A. (2014). Proteomics analysis of cancer exosomes using a novel modified aptamer-based array (SOMAscan) platform. Mol Cell Proteomics, 13(4), 1050-1064. doi:10.1074/mcp.M113.032136

Welton, J. L., Brennan, P., Gurney, M., Webber, J. P., Spary, L. K., Carton, D. G., . . . Clayton, A. (2016). Proteomics analysis of vesicles isolated from plasma and urine of prostate cancer patients using a multiplex, aptamer-based protein array. J Extracell Vesicles, 5, 31209. doi:10.3402/jev.v5.31209

Expensive Doesn’t Always Mean Better: Looking for Ways to Keep Medical Costs Down

A candle flickers. Steam from a loaf of freshly baked bread entwines with the candle smoke like ballroom dancers. I look at the wine list. A loud thud echoes throughout the intimate dining establishment as my jaw hits the floor. One bottle of wine commands a price tag comparable to three times my salary from my first job after college.

I pondered if this expensive wine was truly that superior. I am not the first to ask this question: Numerous others have posed it. Blind taste tests with wine experts are arranged, and a humble wine often prevails over the expensive one (Bell, 2012). In the tests, tasters had used metrics such as cost, winemaker labels or let personal expectations or biases sway their judgement.

These metrics are not only used in assessing wine quality, but also the quality of medical care. The newer, more expensive or fancier the technique, the more effective an intervention must be! Right? But, like the expensive wine, this is not always the truth. Recently, Consumer Reports found that primary-care doctor groups can provide high quality care for a lower cost compared to other groups involved in the analysis (Consumer Reports, 2012).

With healthcare costs sky rocketing and becoming too expensive for many people (even for those with insurance), the topic of cost-conscious care is an imperative one. In an article pertaining to medical waste, newly minted doctors tend to embrace the newest technology, but this technology tends to be pricey (Knowledge@Wharton, 2016). Most of these very same doctors also don’t receive formal training in cost-conscious care. Fortunately, many (but not all) residency programs are incorporating programs pertaining to cost-conscious care (Knowledge@Wharton, 2016).

Aside from learned habits driving the overboard use of unnecessary tests and treatments, fear of litigation can be another driver (Knowledge@Wharton, 2016). While improvements in training or changes to litigation policies may change how doctors approach medicine, improving diagnostic tests or diagnostic protocols may be another alternative that can reduce cost without sacrificing quality. On paper, this sounds achievable through initiatives set forth by the precision medicine movement (Personalized Medicine Coalition, 2017).

Recently, a physical exam regimen highlighted in Sciencemag and offered by Health Nucleus appears to be taking the cost saving opportunities offered by precision medicine in the opposite direction. For a mere $25,000 (This is definitely more than my salary from my first job.), the company offers a medical exam that includes full body magnetic resonance imaging, highly detailed imagery of how well the heart moves blood, other tests that look at heart function, sequencing of the bacteria in the gut, analysis of the metabolites found in the body, genomic sequencing, tests for brain function, and more (Cross, 2017; Health Nucleus, 2017).

A description of the “experience” certainly makes one feel that they are receiving state-of-the-art medical care, but at a high cost. At this price, many insurance companies are not likely to rapidly adopt this type of care. A “bargain package” exists, but costs $7,500 (Cross, 2017). It is doubtful that even Cadillac insurance policies will cover this “bargain” testing.

These expensive diagnostic packages show promise in catching problems early (Perkins et al., 2017), but can researchers produce a diagnostic test that can yield just as comprehensive medical insights at a lower cost? If so, would doctors, patients, and insurance companies readily adopt cheaper, but highly effective tests? Would these lower-cost diagnostics be judged as equivalent or superior to more expensive options? These questions are tougher than deciding which wine to pair with my evening meal. Maybe a blinded assessment is in order?

References

Bell, K. K. (2012). Is There Really A Taste Difference Between Cheap and Expensive Wines? Forbes. Retrieved from https://www.forbes.com/sites/katiebell/2012/07/09/is-there-really-a-taste-difference-between-cheap-and-expensive-wines/#2c42b7253ae2

Cross, R. (2017, May 12) This $25,000 physical has found some ‘serious’ health problems.

Others say it has serious problems. Retrieved from http://www.sciencemag.org/news/2017/05/25000-physical-has-found-some-serious-health-problems-others-say-it-has-serious

Health Nucleus (2017, May) Retrieved from https://www.healthnucleus.com/clinical-tests-and-imaging.

Medical care cost vs. quality: You don’t have to pay the highest prices to get quality care.

Consumer Reports (2012, October). Retrieved from http://www.consumerreports.org/cro/magazine/2012/10/when-costlier-medical-care-isn-t-better/index.htm

Medical Waste: Why American Health Care Is So Expensive. Knowledge@Wharton (2016,

August 18). Retrieved from http://knowledge.wharton.upenn.edu/article/medical-waste-american-health-care-expensive/

Perkins, B. A., Caskey, C. T., Brar, P., Dec, E., Karow, D., Kahn, A., . . . Venter, J. C. (2017). Precision Medicine Screening Using Whole Genome Sequencing And Advanced Imaging To Identify Disease Risk In Adults. bioRxiv. doi:10.1101/133538

The Personalized Medicine Report 2017 Opportunity, Challenges, and the Future. Personalized

Medicine Coalition (2017). Retrieved from http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/The-Personalized-Medicine-Report1.pdf