Daniel Goldman

Revising Public Health Practice

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Sanitation, vaccines, control of various environmental factors that affect health, and much more have greatly improved our quality of life and our average lifespan. But while public health practice has come a long way, there are still numerous areas of improvement. Not only must public health practice improve in terms of communication with the public, but we must also work on improving how quickly scientific knowledge is used to update public health practice. Additionally, public health policy involving zoonotic disease (diseases which are contracted from animals) and protection of the health of livestock and pets, also requires serious attention.

Pseudoscience

The antivax movement, the push for homeopathy, and great deal of other pseudoscientific movements are hurting public health practice. While there’s still lot that we do not know about recent outbreaks of various diseases such as measles and whooping cough, medical science absolutely justifies the use of vaccines in the prevention of dangerous symptoms associated with these diseases. Meanwhile, the link between vaccines and autism has long since been debunked, and yet a large portion of the population still believes in it.

Furthermore, a number of people are choosing to forgo “traditional” medicine and instead use homeopathic treatment. Unfortunately, based on systematic review of available literature, there is no indication that homeopathy works any better than a placebo. There is also no scientific justification for a mechanism through which it should work. Homeopathy literally has every trace of active ingredient diluted out of the product, to the point where a person is just consuming a sugar pill. While the placebo effect can be a powerful medicine in and of itself, it is not a substitute for recognized gold standards of care.

Better science communication, and better education in philosophy, both should improve individual understanding of how science works and acceptance of standard medical treatments. However, there are still other issues. There are cases where our standard of care is outdated.

Living Systematic Review

One of the greatest concerns with public health practice is that it takes a very long time for new scientific evidence to become part of the public health practice. One estimate places the lag time between findings and implementation at 17 years.

Unfortunately, in order to alter public health practice, we need to have more than just a single investigation indicating efficacy. Public health practice relies heavily on systematic reviews. There are two options for systematic reviews. A systematic review can periodically be conducted to see if there’s additional information available. This option is the traditional route. Alternatively, a systematic review can be ongoing, where data is added at regular intervals and the conclusion is reevaluated.

This process is called a living systematic review. This option is fairly new. As of 2017, protocols for the process were still being developed. Elliott JH et al. 2017 discusses the importance of living systematic reviews (LVRs), and suggests that they may be most useful when there’s a lot of new research being done on a topic, when there’s still a lot that we don’t know about the topic, and when new information might change current protocol.

Maintaining Trust

Unfortunately maintaining trust is going to be difficult even if we can update our protocols more quickly. Long standing recommendations being overturned can be problematic because people may wonder why it took so long for the medical community to realize their mistake. Meanwhile constantly changing recommendations to fit new data could establish a view that the medical community is fickle.

People may also become even more confused about what to do for proper health. While this issue isn’t as problematic for people who regularly see a doctor for checkups, some don’t, and current medical recommendations do not actually suggest that they are necessary. This lack of necessity is likely to change if public health policy is updated on a more regular basis though, so this factor needs to be taken into consideration.

Call to Research Format

Even with living systematic reviews, new research needs to be conducted and we need to communicate limitations of existing research. One of the issues that prevents public health policy, and science as a whole, from being as up to date as possible, and evolving at a fast enough pace, is a failure to communicate. I have written numerous papers on concerns about current medical science practices and limitations of our understanding. These papers are not research papers in the normal sense. They fellow what I call the “call to action format.”

Most of my focus has been on vaccines. I’ve written on the issue with understanding recent measles outbreaks, as well as our limited understanding of how asymptomatic infections influence Whooping Cough epidemics. While there is a lot that we know about vaccines and their efficacy, there seems to be a lot that we do not know. And these unknowns are not being discussed in enough detail or frequency to drive new research that can be used to fuel living systematic reviews.

The Format

The first half of the call to research format is similar to a systematic review, but it’s more focused. It looks for specific gaps in our understanding, and summarizes them. It might take into account personal observations by the author, as well as specific questions that they have come across. Questions may also be pulled from existing systematic reviews.

The second half of the paper is a discussion on potential theories on the matter, and studies that can be conducted. The discussion isn’t as detailed as a research proposal, but a single call to research paper could have many suggestions on types of research that can be performed. There should be at least enough detail that a person reading the paper could take the suggestion and turn it into a full research paper.

Zoological Public Health Policy

The second half of this discussion is going to focus on a different aspect of public health. A lot of Americans have pets. While these figures are old, at least as of 2006, approximately 60% of Americans had some kind of pet, according to Gallup. 44% of Americans specifically own a dog, and 29% own a cat. And almost 80% of pet owners have both a dog and a cat.

The lack of information on how many people even have pets is one example of how public health policy needs to be improve. But why is such information important? What do pets have to do with public health? We can look to an article by A. S. Deller, who wrote an interesting piece on zombies, but not quite the zombies of science fiction. Various pathogens alter the brain function of their hosts and actually create what might as well be considered zombies. One such pathogen is Toxoplasma gondii (toxoplasmosis or T. gondii). This pathogen does affect humans, but the way in which it impacts its human hosts is not well known.

According to the CDC, 11% of of the population, aged six and up, have experienced a T. gondii infection. The pathogen can be contracted from eating exposed food, but a major source of infection is zoonotic (animal) sources. While T. gondii doesn’t cause humans to become zombies and seek out cats, it does seem to have neurological effects. In humans, the pathogen seems to be associated with increased risk of psychological conditions such as schizophrenia.

The length in time that it’s taken to even realize the issue, and the lack of protocol developed to deal with it, goes back to the first half of this discussion. Public health policy isn’t being updated fast enough. But the problem also shows that we need to be hyperaware of potential threats from pets, as well as livestock.

There is work being conducted on creating a vaccine for T. gondii, but it’s far from complete. I think that there are two reasons why there is currently no vaccine. One is simply the difficulty in creating the vaccine. The other is in the failure to consider it a problem. Yes, T. gondii infects a lot of our pets, but the public health community never really considered that too much of an issue, because we didn’t consider the potential risk to humans.

But we also need to be more aware of the risks that diseases pose to our pets. We need to make sure that vaccine schedules are up to date, that they receive the right vaccines, enough vaccines, and not too much vaccines. We have a responsibility to protect our pets, because they did not choose to live with us. And therefore public health practice really should dedicate more of its attention to veterinary public health. There are programs available, including MPH-VPH programs, but the attention paid to zoonotic disease, especially risks to pets and risk from pets, simply isn’t enough.

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The Absurd Opposition to Circumcision

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Both the CDC and the WHO have produced recommendations for circumcision. While there isn’t enough information to create a full plan of action, recommending universal circumcision, the science is fairly solid when it comes to counting the claims of anti-circs. I use that term because in many cases, the kind of science denial seen among anti-cutters is no better than that seen among anti-vaxxers. And because of the degree of science denial, and other political issues, I’ve decided to finally write a public health article on the topic.

Why do we know that circumcision is useful? While there’s no absolute in science, there are degrees of justification. The weakest form of justification is personal experience, while the gold standard of scientific research is the double-blind, randomized, placebo-controlled trial. But such trials aren’t always possible. Moreover, in many ways there’s a higher standard. Call it the “platinum standard” if you will: in order to look at efficacy and safety of a treatment, when possible, a systematic review of all available literature should be conducted. This study is essentially a way to test the theory of whether or not there’s enough scientific information to justify a position on a research question. It is a comprehensive, and hopefully largely unbiased analysis of the entire state of the field.

Such a study has been conducted for male circumcision. Two studies of note are Singh-Grewal et al. 2005 and Morris et al. 2017. the researchers found justification for significant efficacy and limited side effects. The first paper looked only at urinary tract infections. Using a simple assumption of equal utility of benefit from treatment and harm from complication, the paper’s findings suggest that circumcision would best be limited to those at high risk of UTI, but indeed that in that sub-population, a significant benefit exists.

Morris et al. takes a broader look at the issue. The 140 journal articles that were analyzed in their systematic review indicated both immediate and long term benefits through the prevention of UTIs, phimosis, diseases caused by poor hygeine, and various STIs. The study looked at the impact of STIs among both sexes, and indicated that females too benefit from male circumcision, through the reduction in transmission of STIs. The study also conducted a risk vs benefit analysis and indicated high benefit and low risk.

One argument against the second paper is that it was written by Morris, who is a vocal supporter of circumcision. But this argument is a genetic fallacy. A paper stands on its own, regardless of who wrote it. What matters is if there is any evidence that the method of the paper itself is flawed. If we are to reject the findings of the study, simply because it was written by a staunch supporter of circumcision, then we should reject pretty much every climate change study and vaccine study, as the authors in these cases are very often associated with organizations that promote various policies related to the two. Indeed, one of the main arguments, used by anti-vaxxers, against a lot of the findings in studies is that the studies were conducted by vaccine supporters, or by or on behalf of the pharmaceutical industry or health organizations that strongly support vaccines.

From an anthropological point of view, it also doesn’t make sense that circumcision would have a net harmful effect, at least not on overall population heath and evolutionary fitness. I’ve pointed out why this condition holds, in some of my other anthropology articles. Natural selection occurs on both the biological and cultural levels. A cultural phenomenon which negatively affects the overall evolutionary fitness of a population in which it exists, tends to die out over time.

A practice which has persisted for 4,000 years is therefore unlikely to have a net negative socioeconomic effect. Indeed, while from the perspective of the people who practiced circumcision, the reason for doing it was because “god said so,” the anthropologist would say that it’s likely that groups that began the practice outperformed those who did not, and thus the practice survived and spread.

American isn’t comparable to Europe. But that won’t stop a lot of people from using the argument that Europe, with its relatively low circumcision rate, also has a relatively low rate of HIV and some other sexually transmitted diseases. The problem with making a direct comparison between these two regions is that they are simply too dissimilar. There are so many other variables that efficacy of the treatment doesn’t necessarily override other factors. For instance, the United States has poor sex education. The war on drugs and refusal to decriminalize drugs also leads to a lot of needle sharing, which spreads HIV and other STIs. Moreover, England has been transitioning to acceptance of homosexuality for a longer period of time than the United States, which allows for better treatment of HIV transmitted through homosexual activities.

Bodily autonomy is another topic of interest for this discussion. I have to admit that bodily autonomy is one of the most basic rights that we have, so violating or circumventing it should be done with caution. We need to look at a number of factors, including net benefit of the treatment, and impact on one’s life going forward. MC seems to have a limited negative impact on quality of life, with a significant benefit to personal and public health. And the argument that bodily autonomy should only be violated, when there is an immediate medical need to treat a current medical issue, also constitutes an argument against childhood vaccination. I’m honestly still a little unsure of how well I can accept any violation of bodily autonomy, but I can at least say that the argument against MC generally constitutes an argument against childhood vaccination as well. And it most certainly constitutes an argument against mandatory vaccination.

Female circumcision, often known as FGM, is the final topic that I’d like to address, as it’s often used as a straw man in my discussions on MC. It might be argued that if my argument holds for MC, it should hold for FC. And maybe it does. If systematic review of scientific literature shows limited negative impact on quality of life, with significant positive impact on personal and public health then it might be possible to argue that FC should be recommended. But FC is far less studied. A couple of studies, most of which are over a decade old, are all we have. Compare that data set to the literally hundreds of studies and multiple systematic reviews on the safety and efficacy of MC.

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Further Discussion on the Measles Outbreak

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In my first article on the measles outbreaks in the Pacific Northwest, I argued that measles vaccination rates have declined little since 1995. Here I’d like to expand on that idea, and comment on specific claims made by various sources.

Is the Washington Post Right?

Twitter seems to have stored a clip that cannot be found in the actual article being linked to in Dr. Pan’s tweet, so I am including it here. According to the summary, “lax state laws have helped drive down vaccination rates across the pacific Northwest.” What the article does state is the following.

The Pacific Northwest is home to some of the nation’s most vocal and organized anti-vaccination activists. That movement has helped drive down child immunizations in Washington, as well as in neighboring Oregon and Idaho, to some of the lowest rates in the country, with as many as 10.5 percent of kindergartners statewide in Idaho unvaccinated for measles. That is almost double the median rate nationally.

So is the article being truthful? Well, I’d say it’s an “alternative fact.” Consider the following graphs.

Washington State Vaccination Rates

I gave an overall analysis of immunization rates at the HHS region and state levels, in my first article. But I want to go into a little more detail about Washington State’s vaccination rates. First off, in the last couple of years, there’s been a rise in volatility, but it’s hard to tell whether this rise is out of the ordinary. When people cite such a short length of time and argue that there’s been a “decline” in vaccination rates, it’s no better than when people look at a few years of cold winters and say “look, the Earth is cooling!” A proper analysis does not look at a few data points. It looks at how those data points compare to the overall known data set.

This graph shows the volatility in the last few years. And perhaps there’s something in the 2012 blip, however it doesn’t seem to be enough to explain the timing of the outbreak, especially since overall vaccination rates are a an average of annual rates. That means that year-by-year variations are smoothed over multiple years.

Better Data Needed

In order to make any more conclusions, a lot more data will be needed. Pockets may be on the county level, or the nodes may be even smaller. If that’s the case, there could still be a change in distribution that my analyses aren’t capturing. But if that’s the case, then it doesn’t seem reasonable that they’d be having such an impact on larger scale outbreaks. We can think of very small communities, within a very large population, almost as individuals.

A Serendipitous Experiment has come out of these recent outbreaks. According to Ars Technica, the recent spike in cases, and widespread attention and concern, has caused a massive increase in vaccinations. So not only should we see an increase in vaccination rates in the coming data sets, but we should see a decline in pockets as well.

Now, the issue is that even if source of the recent outbreaks is something other than the antivax sentiment, we should see a decline in cases, because the vaccine does a good job at preventing symptoms. And that’s why we should ensure that vaccination rates are high. But this result also will cloud any data. A proper analysis would therefore have to adjust for changes in vaccination, if the goal is to see if perhaps the pathogen is becoming more virulent.

Asymptomatic Infection Analysis

Especially because of the recent outbreak and rapid changes in vaccination rates among certain populations, now is the time to take action in analyzing asymptomatic infections. As I’ve mentioned in my paper on whooping cough, asymptomatic infections are poorly understood and studied. While there are certainly differences between whooping cough and measles, and their associated vaccinations, there’s still something we should see, if we took a random sample of the population: infection rates should be significantly lower among vaccinated individuals than in unvaccinated individuals. And how different they are can give us greater insight into how well the current vaccine is working to stop the measles infection.

To give some insight into what we could find, I recently came across a paper studying measles vaccination in Taiwan, presented to me as justification for current understanding of measles vaccination. What the person failed to notice is that based on a random sampling of the population, rather than a survey of cases, it seems that the basic reproduction rate is not driven below one, suggesting an inability to generate herd immunity. One reason that I use “seems” is that I’m currently trying to double check with the authors to see if this was an estimate in the case of 100% vaccination or not.

The disconnect between the apparent “eradication” of measles in the United States, and the general recognition by the medical community that a 95% vaccination rate should generate herd immunity, may suggest that asymptomatic infection is indeed a problem. And that’s why we really need to do a wide-scale analysis in the United States.

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On the Scientific Perception and Reality of Whooping Cough

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The following is a draft research proposal to investigate the scientific perception and reality of the efficacy and efficiency of B. pertussis vaccines and the prevalence of asymptomatic infections. I have written extensively, both on The Spiritual Anthropologist, and over at Politicoid, on the topics of vaccine efficacy and science, especially concerning issues with the way vaccine efficacy is researched and on the potential threat of asymptomatic infections, and have been striving to publish new research, rather than just summarizing existing research.

Systematic Review

Although vaccines against B. pertussis have been around for decades, it has only been in the last decade or so that concerns about the ability for the vaccine to prevent infection have arisen. A small clinical trial involving human primates suggests that the acellular B. pertussis vaccine prevents against clinical symptoms, but may not protect against colonization and transmission of the pathogen. Furthermore, in an observational study, B. pertussis infection was confirmed in Israeli children vaccinated with the whole cell B. pertussis vaccine. Both of these findings bring into question whether or not there is a significant ability for these vaccines to prevent colonization and transmission, or if they can only prevent clinical symptoms. Why did it take so long for the medical community to identify weaknesses in these vaccines? Phase I and II clinical trials should have been able to identify how well the vaccine could prevent the spread of infection. Did B. pertussis evolve to become less affected by the vaccines? Did the researchers fail to consider whether or not the vaccines could prevent infection? Or were the methods that they used incorrect?

One indication that the final situation is actually involved is that at least some studies, which claim that the vaccines are effective at preventing infection, actually can only measure the ability to prevent clinical symptoms. These studies look at case reports or gather their data from patients who have gone to seek medical attention for symptoms. An asymptomatic infection is unlikely to result in a visit to a doctor or hospital, and therefore studies which choose their sample from patients seeking medical attention, rather than from the community as a whole, or which look at symptom prevalence, rather than identifying infection using culture or PCR tests, will only be able to identify how well the vaccine does its job of preventing disease.

A systematic review of available studies on B. pertussis vaccines can help answer the question of whether or not study methodology is at fault. The proposed systematic review will start by searching for all studies which investigate the efficacy and efficiency of B. pertussis vaccines, either whole cell or acellular, whether currently in use or not. Duplicates will be removed, and the studies will be sorted into categories. The categories will be as follows: investigates efficacy, investigates efficiency, sample drawn from general population, sample drawn from those seeking medical attention, identifies symptoms only, identifies infection, comments on ability to prevent infection, and comments on ability to prevent disease. In this way, the study can investigate what fraction of studies have conflated ability to prevent disease with the ability to prevent colonization and transmission. While it is not crucial to the question at hand, a quality analysis will also be conducted to see if there is a relationship between study quality and tendency to conflate these concepts.

The full systematic review will involve two readers. I will not be involved in the review process as the amount of material I have written and read on this specific topic may skew my analysis of the papers.

Model Construction & Parameter Estimation

The basic SVIR model is a useful tool for estimating the dynamics of how infections spread, under various vaccination regimes. However, the model does not take into account how asymptomatic infections, either due to natural partial immunity, or due to partial immunity derived from vaccination, affects epidemics. Parameters that will need to be studied or assumed, before the model becomes viable, include how likely an unvaccinated person is to become asymptomatic upon infection, how likely a vaccinated person is to become asymptomatic upon infection, and how symptoms affect contact rates between healthy and unhealthy individuals.

A key assumption of the model that will be constructed is that appearance of symptoms influences how likely a healthy and infected person are to come into contact with one another. This assumption is based on theories about disease avoidance. Kouznetsova et al. 2011 indicate that such behavior is not limited to actual contagious diseases, but that people will avoid anyone who even appears to be contagious [1]Kouznetsova, Daria, Richard J. Stevenson, Megan J. Oaten, and Trevor I. Case. “Disease-avoidant behaviour and its consequences.” Psychology & Health 27, no. 4 (2012): 491-506. doi:10.1080/08870446.2011.603424.. Risk aversion also occurs in sick individuals. Even though many Americans go to work sick, a significant fraction do stay home or take additional precautionary measures. According to a survey conducted by nsf.org, at least 26% of workers admit to going to work sick. 17% of women and 33% of men admit to always going to work sick. However, those numbers still indicate that a significant number of individuals do stay home, especially if a doctor tells the person to do so.

These results indicate that the rate of contact between healthy and sick individuals is a function of how obvious it is that the person is sick and potentially contagious. Asymptomatic carriers and those with minor symptoms do not appear to be contagious, and might not know that they are sick, and therefore there may be little to no risk avoidance behavior. Ideally, this concept would be modeled using a system of partial differential equations, but ordinary differential equations are much easier to manipulate.

Observational Study

Once parameter estimates are made and the model constructed and evaluated, it will be time to obtain empirical justification of the model. If the model is a reasonable one, it should be able to give us an estimate of the current rate of B. pertussis infection. Even if the model itself fails, the results from obtaining actual estimates for the incidence rates of infection, within the general population, and certain at risk sub-populations, will be useful, both for adjusting the model and for updating public health policy.

The basis of the observational study is a similar study conducted in China. The cross-sectional study attempted to identify the prevalence of asymptomatic infections among school aged students (aged 7 – 15) in four different counties in China. Both culture and PCR testing was used, and sampled were collected between July and September of 2011.

Bibliography

  1. Kouznetsova, Daria, Richard J. Stevenson, Megan J. Oaten, and Trevor I. Case. “Disease-avoidant behaviour and its consequences.” Psychology & Health27, no. 4 (2012): 491-506. doi:10.1080/08870446.2011.603424.
  2. Kurzban, Robert, and Mark R. Leary. “Evolutionary origins of stigmatization: The functions of social exclusion.” Psychological Bulletin 127, no. 2 (2001): 187-208. doi:10.1037/0033-2909.127.2.187.
  3. Srugo, Isaac. “Pertussis Infection in Fully Vaccinated Children in Day-Care Centers, Israel.” Emerging Infectious Diseases6, no. 5 (2000): 526-29. doi:10.3201/eid0605.000512.
  4. Fulton, T. Roice, Varun K. Phadke, Walter A. Orenstein, Alan R. Hinman, Wayne D. Johnson, and Saad B. Omer. “Protective Effect of Contemporary Pertussis Vaccines: A Systematic Review and Meta-analysis.” Clinical Infectious Diseases 62, no. 9 (2016): 1100-110. doi:10.1093/cid/ciw051.
  5. Warfel, J. M., L. I. Zimmerman, and T. J. Merkel. “Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model.” Proceedings of the National Academy of Sciences 111, no. 2 (2013): 787-92. doi:10.1073/pnas.1314688110.
  6. Zhang, Qi, Zundong Yin, Yixing Li, Huiming Luo, Zhujun Shao, Yuan Gao, Li Xu, Biao Kan, Shan Lu, Yan Zhang, Manshi Li, Meizhen Liu, Pingping Yao, Zhixian Zhao, and Qiushui He. “Prevalence of asymptomatic Bordetella pertussis and Bordetella parapertussis infections among school children in China as determined by pooled real-time PCR: A cross-sectional study.” Scandinavian Journal of Infectious Diseases 46, no. 4 (2014): 280-87. doi:10.3109/00365548.2013.878034.

Webpages

https://www.nsf.org/newsroom_pdf/Flu_in_the_workplace_(final).pdf

http://www.nsf.org/consumer-resources/studies-surveys-infographics/consumer-survey-results/flu-in-workplace

 

References   [ + ]

1. ↑ Kouznetsova, Daria, Richard J. Stevenson, Megan J. Oaten, and Trevor I. Case. “Disease-avoidant behaviour and its consequences.” Psychology & Health 27, no. 4 (2012): 491-506. doi:10.1080/08870446.2011.603424.

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The Human Gut Microbiome

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Introduction

Over the last couple of decades, we have learned a lot about the human gut microbiome. Rather than simply being a collection of commensal organisms, the gut microbiome (GMB) is now thought to be involved in a number of important metabolic roles, including nutrient extraction, immunity, and possibly even the regulation of sleep and mood. The degree with which negative health outcomes have been associated with a dysbiosis, or the dysfunctional GMB, and the degree with which different organ systems interact with the GMB, suggest that we should consider it to be as important as an organ, if not actually an organ itself. Dysbiosis is therefore not a minor inconvenience that may cause discomfort, but a syndrome or disease that must be treated to maintain proper health. Further research on gut microbiome dysbiosis should be undertaken, including research into new diagnostic tools. The first half of the paper will summarize part of the discoveries made in the field of research on the GMB. The second half of the paper will use those findings to suggest further research.

Overview of the Field

The human GMB is fairly diverse. On average, the human gut contains well over 1,000 species-level phylotypes (Lozupone et. al. 2012). But that is only on the individual level. According to Jandhyala et al. (2015), those species are from a pool of over 35,000 total species level phylotypes that have been identified as being found in human guts. But even with that diversity, there seems to be two main phyla present: Bacteroidetes and Firmicutes. Bacteroidetes are gram negative while Firmicutes are gram positive. Overall, these microbes are not just commensal but are responsible for a number of metabolic functions within the gut. Bacteroides, a genus in the phyla Bacteroidetes, “are the predominant organisms that participate in carbohydrate metabolism (Jandhyala et al. 2015).” A key species in this genus is B. thetaiotaomicron. These organisms process carbohydrates “by expressing enzymes such as glycosyl transferases, glycoside hydrolases and polysaccharide lyases (Ibid.).”

There are a number of useful byproducts generated by these industrious workers. “Fermentation of the carbohydrates that escaped proximal digestion and indigestible oligosaccharides by colonic organisms such as Bacteroides, Roseburia, Bifidobacterium, Faecalibacterium, and Enterobacteria result in the synthesis of short chain fatty acids (SCFA) such as butyrate, propionate and acetate, which are rich sources of energy for the host[35,36].” (Ibid) Additionally, vitamin K along with precursors to vitamin B are produced within the gut (Ibid). Furthermore, as indicated in Mahony et al. (2014), the GMB is associated with mood and sleep, through the gut-brain axis. This connection seems to be due, at least in part, to the production of serotonin from tryptophan in the gut (Mahony et al. 2014). However, as addressed in Carabotti et al. (2015), the interaction is not mono-directional. The brain influences numerous gut functions, including “motility, secretion of acid, bicarbonates and mucus, intestinal fluid handling and mucosal immune response” (Carabotti et al. 2015). Many of the bacteria in our gut also have receptors for neurotransmitters, such as GABA (Ibid.).

The importance of the many apparent functions of the GMB are consistent with the much narrower range found in functional diversity, as opposed to phylogenetic diversity, within the gut: “despite having highly divergent gut microbiota compositions, functional gene profiles are quite similar in different individuals” (Lozupone et al. 2012). The specific roles of our  microbiota may also explain another interesting result. While Bacteroidetes and Firmicutes are the most common phyla of microbes present, the ratio of these organisms varies considerably depending on a number of factors, including diet. Looking at healthy individuals, Firmicutes were the most dominant phyla in vegetarians, while in non-vegetarians, Bacteroidetes were the most common phyla (Bamola et al. 2017). This variation is reasonable since different foods would require different microbes to process them.

So diet influences the human gut microbiome. But that microbiome needs to be established in the first place. Some of our GMB is colonized very early in our lives. Roughly 25% of infant gut bacteria come from breastmilk and microbes found on the breast of the mother (Pannaraj et al. 2017). Microbial composition then varies considerably for the first few years, increasing in overall diversity until the ecosystem finally stabilizes (Lozupone et al. 2012).

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Placebo as Medicine

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Why do people view the placebo effect as if it’s “no effect?” Consider the following quote by Steven Novella, MD over at “Science Based Medicine.”

These placebo effects include: Regression to the mean – when symptoms flare, they are likely to return to baseline on their own. If you take any illness that fluctuates in severity, any treatment you take when your symptoms are at their peak is likely by chance alone to be followed by a period of less intense symptoms.

This is incorrect. The placebo effect is not an incorrect statistical analysis, or an incorrect assignment of natural variation to treatment. Placebo means that there is no pharmacological effect, but this does not mean that there is no effect.

A real placebo effect is a psychobiological phenomenon occurring in the patient’s brain after the administration of an inert substance, or of a sham physical treatment such as sham surgery, along with verbal suggestions (or any other cue) of clinical benefit (Price et al, 2008). Therefore, the effect that follows the administration of a placebo cannot be attributable to the inert substance alone, for saline solutions or sugar pills will never acquire therapeutic properties. (How Placebo’s Change the Patient’s Brain)

I think Novella is confusing apparent and actual placebo effects. A placebo group can appear to show results, as can an actual treatment group, due to statistical noise, methodological error, etc. But an apparent change between pre-outcome and post-outcome means is not the placebo effect. Only an actual change in initial and final condition within the plaebo group is an actual placebo effect. This effect is a measurable effect and induces a measurable change in brain activity, as shown in fMRIs. And quite frankly, in some ways it does not matter whether or not an improvement in health is due to the drug itself or the belief that the drug works.

If someone has a blood pressure reading of 180/110 and because they believe a sugar pill works, it goes down to 130/80, that’s a life saving shift. Obviously there is the question of whether or not the effect will continue to work. A placebo may wear off as the person’s belief changes, etc. However, this can also happen for a drug which has its own effect. That effect can be boosted by the placebo effect, which is why we do not say that a treatment has no effect, but rather no effect different from the placebo. In fact, going back to the example of blood pressure, a meta analysis of 23 trials for beta-blockers concluded that “the placebo response accounted for 34% of the drug response for sBP and 47% of the drug response for dBP (Effect of placebo groups on blood pressure in hypertension: a meta-analysis of beta-blocker trials).”

But maybe that effect is simply due to regression to mean or some kind of sampling error. To see if that is the case, a study comparing placebo treatment to no treatment can be performed. This has been done and a difference between placebo treatment and no treatment has been found. (Evaluation of the placebo effect and reproducibility of blood pressure measurement in hypertension) Admittedly, this study is weak, but i is also unnecessary.

The argument that results from the meta-analysis were due to sampling error, regression to mean caused by natural recovery, etc are all unlikely. People with hypertension do not tend to recover on their own. Hypertension is a chronic issue. Also, while there is some variability in blood pressure based on method of reading, time of day, etc, a large sample reduces these statistical anomalies from clouding data. In order for difference of means to be due to regression to mean or other sampling error, individual patients’ blood pressures would have to have varied wildly throughout the studies. Additionally, the meta analysis cited above uses a moderator analysis to compare factors like sample size and trial duration, and found that better quality trials resulted in stronger apparent changes in the placebo group. This is contrary to what one would expect if the apparent change in the placebo group was actually do to factors like sampling, regression to mean, or poor quality control.

Another way to test for the existence of an actual placebo effect is to try to look at cognitive signatures. At least one study has found a relationship between the placebo effect and mu opioid receptors (Chronic mu-opioid receptor stimulation alters cardiovascular regulation in humans: differential effects on muscle sympathetic and heart rate responses to arterial hypotension). Another study created a predictive model using the data from one trial and successfully predicted level of placebo in a second trial (Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials).

All together, we have multiple studies that look at the placebo effect in different ways. In addition to results from clinical trials on drug treatments, we also have a proposed mechanism and data consistent with that mechanism. The ability to create a model predicting strength of the placebo effect, the increase in strength of placebo effect as quality of the study increases, and a proposed mechanism all together make the theory that there is a real placebo effect robust.

Beyond the placebo effect, the nocebo effect could result in a normally effective drug becoming ineffective. View towards the treatment therefore needs to be taken into account and we need to make sure that the placebo component of the drug’s effect does not wane, or at least compensate for its waning, and we need to make sure that view towards treatment is not negatively effecting outcome.

Research Ideas

There are a few research ideas that arise from this discussion. First, if placebo and nocebo can have a considerable impact on certain treatments, we should know this. Skepticism towards standard medicine is increasing and that might have a negative impact on efficacy of certain treatments. To test this effect, we can perform a few clinical studies that measure how positive or negative the patient’s view is towards medicine in general and towards the treatment. If perception has a significant effect, then we would expect the placebo to result in greater positive results among those who positively score medical treatment and weaker, or maybe even negative effects, among those who negatively score medical treatment.

A few additional questions can also be asked, such as whether or not the patient believed he received an actual treatment or a placebo. In order to reduce the risk of how the question of skepticism influences results, some patients should be asked at the beginning of the test, some at the end, and some at both points. This variation will reduce noise caused by expectation generated by the question being asked. The sample size would have to be fairly large in order to make sure that enough data on each sub-sample is collected. While pain medication may show the most robust results, continuing with a less obvious condition like hypertension might be preferred. There are a number of high blood pressure medications which are considered relatively safe and therefore are reasonable for large scale clinical trials.

Because perception of efficacy is important, the patients should be blinded from seeing their blood pressure results.

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