Monday, February 27, 2017

Should patient data that could be used for lifesaving research be freely available to any researchers that want it?

Question refers to this Newsweek article: http://www.newsweek.com/2016/07/29/war-over-cancer-patient-data-myriad-481608.html


Anonymized patient data is already easily and legally available to the highest bidder, if one knows where to look. But its use in research isn't as much of a priority among the main healthcare data brokers as is making money off of it. Thus, at the intersection of business and science of health, there are currently three main approaches towards health data sharing, the first two prioritizing business while the last one prioritizes science,
  • Hold on to patients' health data as tightly as possible as if it were the proverbial gold mine, an approach exemplified by Myriad Genetics, also the approach discussed in the Newsweek article referenced in the question.
  • Sell it behind the scenes to the highest bidder, all legally of course, an approach exemplified by IMS Health.
  • Partner with academic partners and share it fully with them, an approach exemplified by 23andMe.
Which course(s) will prevail will depend on how the politics of health plays out, specifically future legislation and the outcome of legal challenges to any or even every one of these three prevailing approaches.

The Health Data Marketplace Where Anonymized Patient Dossiers Are Freely Bought & Sold
In a Feb 2016 Scientific American article (1), Adam Tanner states that IMS Health dominates the medical data trading industry. Apparently it automatically receives Petabyte (>10^15), yes with a p, of data from computerized records of pharmacies, insurance companies, and medical organizations including US federal and state health departments. Specifically, Tanner states that 3/4ths of all retail pharmacies in the US send some portion of their electronic records to IMS Health but that's not all.
According to Tanner, IMS Health itself claims to have half a billion individual patient 'dossiers' from the US to Australia. Anonymized to protect patient privacy, they're stripped of individual identifiers such as social security numbers, names, addresses. This way, data transfer to and from IMS Health and other data brokers doesn't violate medical privacy rules such as the 1996 US Health Insurance Portability and Accountability Act (HIPAA), which applies only to transfer of medical information directly tied to a patient's identity.

Even anonymized, such data's extremely lucrative. For example, Tanner's article (1) quotes Marc Berger who heads the analysis of anonymized patient data at Pfizer as saying it annually pays US $12 million to buy health data from a variety of sources including IMS Health.

As well, the public is largely unaware of the extent to which such companies go to maintain their business practices. For example, HIPAA only applies to patient records, not to doctors' prescribing habits. Starting in the 1990s, IMS Health started selling US doctors' prescribing data. Obviously this helps pharma companies tailor their sales pitches to individual doctors. According to Tanner, even though 36 US states, the US Department of Justice and advocacy groups challenged such a practice, IMS Health fought all the way to the US Supreme Court and prevailed in 2011 on the grounds of corporate 'free speech' (2). Upshot? Even today, US doctors' prescribing habits are up for grabs, sold and traded freely in the marketplace.

One bright spot in this otherwise bleak story? IMS Health also shares some data for free or at a discount with academia. As proof of its academic partnerships, IMS Health's web-site offers a browsable database of >3000 scientific publications (3) they claim span 'virtually all therapy areas and projects completed in more than 50 countries worldwide' (4).

Health Data Privacy Concerns: Anonymized Data's Not Always So Anonymous
In a famous example from 1997 (5), back when she was still a graduate student, Latanya Sweeney identified then Massachusetts Governor William Weld through publicly available hospital records. Apparently all it took for her to identify him from anonymized hospital records was to compare them with the voter registration rolls for the governor's city of residence, Cambridge, MA. Doing so, Sweeney was able to pinpoint records based on age and gender that could only pertain to Weld. This included a recent hospital visit, diagnosis and prescriptions.

Of course, Weld being a public figure with a highly publicized hospitalization obviously helped Sweeney succeed in rather easily re-identifying him (6).

As an outcome of Sweeney's re-identification of Weld, important changes were made to HIPAA. These include public records now including only 3-digit rather than 5-digit zip code and only year, not year and day of birth. These changes do make it more difficult to re-identify people from anonymized patient data (7).

Despite such changes, it's still possible to re-identify medical research study participants (see table below from 8).



While people like George M. Church and Steven Pinker are openly unconcerned about their health data privacy (9), human history provides compelling countervailing examples of research abuse in the form of Nazi experimentation and the Tuskegee syphilis experiment. Scope for health data misuse can't simply be wished away. Instead, such misuse can only be thwarted by improving or expanding scope of specific laws. For example, today in the US, the HIPAA Privacy Rule only covers government-funded research but could be expanded to cover the private sector as well (10).

The 23andMe Model: Share Patient Data With Academics To Advance Medical Research
In the 23AndMe model, people send it their saliva and consent to allow it to use anonymized information derived from it for research.

In the most recent example, their collaboration with researchers from the Massachusetts General Hospital and the University of Pennsylvania, published in Nature Genetics, studied 75607 self-reported depressive individuals with 231747 healthy controls, and identified 17 independent Single-nucleotide polymorphism from 15 genetic loci associated with risk of major depression in people of European ancestry (11).

Interesting nuggets from this study include overlap with genetic regions involved in neuronal development, schizophrenia, neuroticism. This suggests future studies examining these conditions in tandem may yield more insights.

Caveat about 23AndMe samples is the scientific one about the source, i.e., saliva. Presence of digestive enzymes and microbes makes saliva less reliable than blood.

While such data is very far from helping provide patients better Rx, it's part of the process involved in the first step necessary for improved medicine, namely, identifying specific genomic targets for Rx.
As well, 23AndMe's approach is certainly refreshing considering how business-related profit motive prevails among dominant players like IMS Health in the health data marketplace.

Summation
In short, the extremely lucrative market for legally buying and selling patient data proves it's already perceived to be quite valuable. Many of us are simply unaware of the extent of this marketplace or even that it exists at all. 23AndMe's proactive partnering with academia, while laudable, is very much an outlier. Such practices can only become the norm if the public actively pushes their governments to make it so through legislation. For that to happen, first the fact that anonymized patient data is already freely legally bought and sold needs to become common knowledge. Understandably the major operators assiduously fly under the radar, careful not to attract undue attention. Onus is on the media to highlight this practice of legally buying and selling health data records, and for the public to fully inform itself of its pros and cons, obviously mainly cons. Another option, already being practiced by the Framingham Heart Study and by the US state of Rhode Island, is to offer study participants the option of choosing to forbid collection of their medical information for commercial use (1). Again such options can only become more mainstream with greater public awareness of the dangers of unfettered market control of patient health data, a situation that's not theoretical but rather, as the examples of Myriad Genetics and IMS Health show, already a practical reality.

Bibliography
1. Tanner, Adam. "For Sale: Your Medical Records." Scientific American 314.2 (2016): 26-27. How Data Brokers Make Money Off Your Medical Records
5. Sweeney, Latanya. "k-anonymity: A model for protecting privacy." International Journal of Uncertainty, Fuzziness and Knowledge-Based Systems 10.05 (2002): 557-570. http://www.cs.colostate.edu/~cs6...
6. Barth-Jones, Daniel C. "The're-identification' of Governor William Weld's medical information: a critical re-examination of health data identification risks and privacy protections, then and now." Then and Now (July 2012) (2012). https://fpf.org/wp-content/uploa...
7. Techpinions, Steve Wildstrom, July 9, 2012. Can You Be Identified from Anonymous Data? It’s Not So Simple
8. Milius, Djims, et al. "The International Cancer Genome Consortium's evolving data-protection policies." Nature biotechnology 32.6 (2014): 519-523.
10. Contreras, Jorge L. "The president says patients should own their genetic data. He's wrong." Nature Biotechnology 34.6 (2016): 585-586.


Sunday, February 19, 2017

Does the recent breakthrough in ALS suggest we should be looking for more opportunities for Ice Bucket Challenges?


Could this study have been done without Ice Bucket Challenge funding? Based on evidence from the study itself, it seems safe to infer yes.

The science behind the ALS-Ice Bucket Challenge news reports: On July 25, 2016, the scientific journal Nature Genetics published a letter that identified variants of a gene linked to Amyotrophic lateral sclerosis / Motor neuron disease (1). With ~95 authors from ~12 countries, this large-scale study suggests loss-of-function risk variants in the NEK1 gene may be present in ~3% of European and European-American ALS/MND cases. In other words, these researchers may or may not have identified something that may or may not help develop a Rx at some time in the future, a Rx by the way that would be of relevance to less than 3 out of 100 ALS/MND patients of European ancestry. Thus, obviously a valuable thread to help unravel the mystery of ALS/MND but not exactly a breakthrough.

Problems With News Reports About This Study: Misleading & Inaccurate
Looks like another case of excessive media over-reach. Comparing three news reports about this study, one in Endgadget (The internet's Ice Bucket Challenge funded a medical discovery), another in the Guardian (Remember the ice bucket challenge? It just funded an ALS breakthrough) and a third in the BBC (Ice Bucket Challenge funds gene discovery in ALS (MND) research - BBC News), with information from the study itself shows all three news reports had the same two problems,
  • One, they erroneously imply money raised by the Ice Bucket Challenge solely funded this research. Something so far from being true as to be utterly ludicrous and outright misleading.
    • The study itself clearly shows it was funded quite conventionally by government agencies and foundations, and in addition, by Project MinE, which was funded by the Ice Bucket Challenge.
    • So many different entities funded it, its Acknowledgments section itself occupies ~14% of the total paper length.
    • Funders listed include the US National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS), the American ALS Association, the Motor Neuron Disease (MND) Association, the Angel Fund, Project ALS/P2ALS, the ALS Therapy Alliance, The Netherlands ALS Foundation (Project MinE), ALS liga Belgium, Suna and Inan Kirac Foundation as well as government agencies in Australia, Belgium, Germany, Italy, Spain, the Netherlands, the UK.
    • Project MinE supported the study's 2nd last and Corresponding author, Jan H. Veldink, and his colleague Leonard H van den Berg, both at the Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands. This is one of forty-four academic affiliations listed in this study. Eight of the ~95 authors listed in this study are affiliated with this Centre.
  • Two, they fail to mention something the study itself rightfully points out, that it builds on two previous reports that already linked Nek1 variants to ALS/MND risk (2, 3).
So yet another example, if ever we needed one more, to not take news media reports about a scientific article at face value. Given the number of scientific papers published every day, an obvious question is why this one stoked so much disproportionate media attention. Some kind of PR blitz likely worked behind the scenes. Too bad the actual data don't support its spin. Problem is this answer's unlikely to change that. Like a genie freed from the bottle, the spin that the Ice Bucket Challenge 'worked' is already the established media narrative. Another example of the nexus between media organizations and PR campaigns motivated on behalf of specific science stories. And the truth? That doesn't even get the chance to make it past the starting gun.

Bottomline, this study didn't depend solely on the Ice Bucket Challenge funding and could have been done without it.

Bibliography
1. Kenna, Kevin P., et al. "NEK1 variants confer susceptibility to amyotrophic lateral sclerosis." Nature Genetics (2016).
2. Cirulli, Elizabeth T., et al. "Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways." Science 347.6229 (2015): 1436-1441. http://www.ncbi.nlm.nih.gov/pmc/...
3. Brenner, David, et al. "NEK1 mutations in familial amyotrophic lateral sclerosis." Brain 139.5 (2016): e28-e28. https://www.researchgate.net/pro...


https://www.quora.com/Does-the-recent-breakthrough-in-ALS-suggest-we-should-be-looking-for-more-opportunities-for-Ice-Bucket-Challenges/answer/Tirumalai-Kamala


Sunday, February 12, 2017

Where do various biotechnologies exist on the hype cycle for academic research and industrial research /manufacturing?


To start with, the Hype cycle is an entertaining but inaccurate model so to accept it unquestioningly is itself a problem.

As far as excessive or overenthusiastic promotion of these various biotechnologies is concerned, to add to Ian Welland's summation, Immunotherapy, and specifically Cancer Immunotherapy, currently seem to be coming off of peak hype, given the back-to-back reports of clinical trial deaths from Juno Therapeutics and ZIOPHARM Oncology in early and mid-July 2016, respectively.

Exploring the question's assumptions is a more interesting exercise.
  • First, this wording, 'What changes need to be made to reach the plateau of productivity?' suggests a problematic assumption, that not only might a generic tool-kit exist but much like a magic wand, could be easily deployed to any over-hyped technology and so doing, could in short order make the process of its widespread adoption submit to rationality and render it more efficient. Doesn’t such an excessively technocratic approach contradict the way human societies really operate, which on the contrary reveal themselves to be much too haphazard and unpredictable? After all, were the latter not the case, would hype even exist?
  • Next, the unquestioning acceptance that the hype cycle 'model' accurately represents how societies adopt technological innovations is also problematic. Where's the proof the hype cycle's even accurate?
    • The problem with the hype cycle is it combines two separate phenomena, one, the fallible human tendency to fetishize novelty and all that entails such as contagion, excessive enthusiasm, speculation, in short, hype, and two, the classic S-curve that describes the Diffusion of innovations.
    • In a recent meta-analysis of empirical studies on the hype cycle (1), Dedhayir and Steinert emphasize that one of its key weaknesses is it melds these two disparate phenomena that measure different outputs, and artificially forces on them the same y-axis parameter, namely, visibility (or expectations).
    • The human hype-centric cycle typically assesses enthusiasm for the new technology. How to measure enthusiasm? This remains unclear since the hype cycle measures it using two different y-axes interchangeably, namely, visibility and expectation, which have different operational definitions. While visibility is defined as 'technology presence rate on media channels, conversations as well as in interpersonal conversations', expectation is defined as 'expected future value of an innovation' (1).
    • Meantime, the S-curve for assessing diffusion of innovations measures neither enthusiasm nor visibility nor expectations but rather the innovation's rate of adoption.
    • No wonder then that the resulting model doesn't have a track model for successful predictions which is what this recent meta-analysis also suggests (see below from 1).
A Meta-Analysis Suggests The Hype Cycle's A Flawed Model Found In <50% Of Empirical Results


Bibliography
1. Dedehayir, Ozgur, and Martin Steinert. "The hype cycle model: A review and future directions." Technological Forecasting and Social Change 108 (2016): 28-41. https://www.researchgate.net/pro...


https://www.quora.com/Where-do-various-biotechnologies-exist-on-the-hype-cycle-for-academic-research-and-industrial-research-manufacturing/answer/Tirumalai-Kamala


Sunday, February 5, 2017


Over the years, the consensus that harms of antibacterial soaps outweigh their benefits has indeed coalesced. But to understand how antibacterial soaps could harm, we first need to understand how they differ from regular soaps. Also referred to as antimicrobial or antiseptic soaps, they contain chemicals that regular soaps don't.

Many liquid soaps labeled antibacterial contain Triclosan, a synthetic compound, specifically a phenylether or chlorinated bisphenol. While the US FDA classifies it as a Class III drug, i.e., a compound with high solubility and low permeability, Triclosan is also a pesticide. Triclocarban is another common chemical found in antibacterial soaps. Many of the concerns about Triclosan also apply to Triclocarban (1).

Since it appeared on the scene in 1972, Triclosan has steadily permeated through the consumer landscape such that it's practically ubiquitous today (see lists below from 1 and 2).


Triclosan's so ubiquitous it's even found embedded in medical devices such as catheters and sutures to prevent infections (3).

As for its beneficial effect, a 2015 study compared bactericidal effect of plain versus Triclosan-containing soaps in conditions that mimic hand washing, and found no difference in their ability to reduce bacterial numbers during a 20 second exposure (4). In other words, dubious benefit when used for routine hand washing under normal circumstances, i.e., only washing hands for a few seconds. After all, most of us don't scrub as though preparing to do surgery every time we wash our hands.

How Triclosan, A Common Antibacterial Soap Ingredient Inhibits/Kills Microbes
In vitro studies show Triclosan can stop bacteria growing at low concentrations (bacteriostatic), and kill them at high concentrations (bactericidal). It also has some activity against some fungi (5) and even parasites such as those that cause malaria, Plasmodium falciparum, and toxoplasmosis, Toxoplasma gondii (6).

Triclosan is able to target many different types of bacteria by blocking the active site for an enzyme essential for bacterial fatty acid biosynthesis (7, 8). Blocking the enzyme enoyl-acyl carrier protein reductase, Triclosan prevents bacteria from synthesizing fatty acid, which they need for their cell membranes and for reproduction.

Problems With Triclosan
I. Triclosan selects for antibiotic resistance
As widespread Triclosan use increased, labs increasingly started finding cross-resistance to antibiotics. Under selection pressure from Triclosan, bacteria mutate to develop resistance mechanisms to it, which end up bestowing antibiotic resistance as well. In other words, studies show Triclosan selects for antibiotic resistance (see table below from 9).


II. Discharged Widely Into The Environment, Triclosan Can Affect Biomass Such As Algae & Bacterial Communities
Since it's widely used in such a diverse array of products, Triclosan ends up in soil, ground water and municipal wastewater treatment plants. Such plants require proper functioning of microbes to break down sewage. Triclosan can inhibit methane production in wastewater plant anaerobic digesters as well as select for multidrug resistance in such bacterial communities (10). Triclosan's effects persist even beyond because it's discharged from wastewater treatment plants as effluent. Certain algae species in the vicinity of such plants have been found to be very sensitive to Triclosan (11, 12). Triclosan also affects bacterial communities in rivers (13). Potential environmental risk of Triclosan becomes even more relevant in areas of water scarcity where it doesn't get sufficiently diluted.

III. Triclosan Can Alter Gut Microbiota In Fishes & Rodents, Potentially Alter Human Microbiota, & Even Promote Tumors In Rodents
  • Triclosan could profoundly (14) and stably (12) alter fish gut microbiota as well as those of baby rats (15).
  • While so far Triclosan doesn't appear to affect human gut microbiome, the data are far from conclusive, being based on just one study with 7 volunteers (16). OTOH, a study on nasal secretions from 90 healthy adults found a positive correlation between presence of Triclosan in nasal secretions and nasal colonization by Staphylococcus aureus (17). This suggests Triclosan indeed has the potential to influence, even alter human microbiota.
  • One mouse model even found Triclosan capable of promoting liver tumors (18).
IV. Triclosan Can Disrupt Hormonal Function
Triclosan was found to disrupt thyroid hormone-associated gene expression and altered the rate of frog metamorphosis (19). It could also disrupt thyroid (20, 21), estrogen (22), and testosterone (23) function in rats.

V. Triclosan Bans
Given the increasing litany of concerns about Triclosan's deleterious effects on the physiology of a wide variety of species, which may also increasingly include humans, several governments are either considering banning it or have already done so.
  • In March 2010, the European Union banned Triclosan from any products that may come into contact with food (2).
  • On 16 May, 2014, the US state of Minnesota banned the sale of Triclosan-containing cleaning products (soaps), giving manufacturers time until early 2017 to phase them out (24).
  • As of 2015, Health Canada was considering banning Triclosan. It's estimated ~1730 products including cosmetics, health and personal care products containing Triclosan were available in Canada in 2011 (1).
  • The US FDA is mulling its regulation (25), with a report due in September 2016.
Bibliography
1. Dhillon, Gurpreet Singh, et al. "Triclosan: current status, occurrence, environmental risks and bioaccumulation potential." International journal of environmental research and public health 12.5 (2015): 5657-5684. Triclosan: Current Status, Occurrence, Environmental Risks and Bioaccumulation Potential
2. Alliance for the Prudent Use of Antibiotics. "Triclosan." White Paper prepared by the Alliance for the Prudent Use of Antibiotics (APUA) (2011). http://emerald.tufts.edu/med/apu...
3. Stickler, David James, G. Ll Jones, and Allan Denver Russell. "Control of encrustation and blockage of Foley catheters." The Lancet 361.9367 (2003): 1435-1437. http://carambola.usc.edu/Biofilm...
4. Kim, S. A., et al. "Bactericidal effects of triclosan in soap both in vitro and in vivo." Journal of Antimicrobial Chemotherapy (2015): dkv275.
5. Vischer, W. A., and J. Regös. "Antimicrobial spectrum of Triclosan, a broad-spectrum antimicrobial agent for topical application." Zentralblatt für Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene. Erste Abteilung Originale. Reihe A: Medizinische Mikrobiologie und Parasitologie 226.3 (1974): 376.
6. McLeod, Rima, et al. "Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of Apicomplexan Fab I." International journal for parasitology 31.2 (2001): 109-113. https://www.researchgate.net/pro...
7. McMurry, Laura M., Margret Oethinger, and Stuart B. Levy. "Triclosan targets lipid synthesis." Nature 394.6693 (1998): 531-532.
8. Levy, Colin W., et al. "Molecular basis of triclosan activity." Nature 398.6726 (1999): 383-384.
9. Schweizer, Herbert P. "Triclosan: a widely used biocide and its link to antibiotics." FEMS microbiology letters 202.1 (2001): 1-7. http://femsle.oxfordjournals.org...
10. McNamara, Patrick J., Timothy M. LaPara, and Paige J. Novak. "The impacts of triclosan on anaerobic community structures, function, and antimicrobial resistance." Environmental science & technology 48.13 (2014): 7393-7400. https://www.researchgate.net/pro...
11. Reiss, Richard, et al. "An ecological risk assessment for triclosan in lotic systems following discharge from wastewater treatment plants in the United States." Environmental Toxicology and Chemistry 21.11 (2002): 2483-2492.
12. Lawrence, J. R., et al. "Resilience and recovery: The effect of triclosan exposure timing during development, on the structure and function of river biofilm communities." Aquatic Toxicology 161 (2015): 253-266. https://www.researchgate.net/pro...
13. Ricart, Marta, et al. "Triclosan persistence through wastewater treatment plants and its potential toxic effects on river biofilms." Aquatic Toxicology 100.4 (2010): http://www.clipmedia.net/galera/...
14. Narrowe, Adrienne B., et al. "Perturbation and restoration of the fathead minnow gut microbiome after low-level triclosan exposure." Microbiome 3.1 (2015): 1. Microbiome
15. Hu, Jianzhong, et al. "Effect of postnatal low-dose exposure to environmental chemicals on the gut microbiome in a rodent model." Microbiome 4.1 (2016): 1. Microbiome
16. Poole, Angela C., et al. "Crossover Control Study of the Effect of Personal Care Products Containing Triclosan on the Microbiome." mSphere 1.3 (2016): e00056-15. http://msphere.asm.org/content/m...
17. Syed, Adnan K., et al. "Triclosan promotes Staphylococcus aureus nasal colonization." MBio 5.2 (2014): e01015-13. Triclosan Promotes Staphylococcus aureus Nasal Colonization
18. Yueh, Mei-Fei, et al. "The commonly used antimicrobial additive triclosan is a liver tumor promoter." Proceedings of the National Academy of Sciences 111.48 (2014): 17200-17205. http://www.pnas.org/content/111/...
19. Veldhoen, Nik, et al. "The bactericidal agent triclosan modulates thyroid hormone-associated gene expression and disrupts postembryonic anuran development." Aquatic Toxicology 80.3 (2006): 217-227. https://www.researchgate.net/pro...
20. Crofton, Kevin M., et al. "Short-term in vivo exposure to the water contaminant triclosan: evidence for disruption of thyroxine." Environmental Toxicology and Pharmacology 24.2 (2007): 194-197. https://www.researchgate.net/pro...
21. Zorrilla, Leah M., et al. "The effects of triclosan on puberty and thyroid hormones in male Wistar rats." Toxicological Sciences 107.1 (2009): 56-64. The Effects of Triclosan on Puberty and Thyroid Hormones in Male Wistar Rats
22. Stoker, Tammy E., Emily K. Gibson, and Leah M. Zorrilla. "Triclosan exposure modulates estrogen-dependent responses in the female wistar rat." Toxicological Sciences (2010): kfq180. Triclosan exposure modulates estrogen-dependent responses in the female Wistar rat
23. Kumar, Vikas, et al. "Alteration of testicular steroidogenesis and histopathology of reproductive system in male rats treated with triclosan." Reproductive Toxicology 27.2 (2009): 177-185.
25. Kuehn, Bridget M. "FDA pushes makers of antimicrobial soap to prove safety and effectiveness." JAMA 311.3 (2014): 234-234.


https://www.quora.com/Does-anti-bacterial-soap-do-more-harm-than-good/answer/Tirumalai-Kamala