Lies, damn lies and statistics

This was going to be a post about THC, but the recent dust-up over the FDA’s emergency approval of convalescent plasma to treat Covid-19 has encouraged me to deal with this subject as a more pressing topic. We are going to discuss the use of statistics in medicine. While I know that sounds dull, trust me, it is important to all of us, not just to doctors.

Picture this. 100 people come to my clinic complaining of fever and a cough. All hundred test positive for Covid-19. I give all of them a secret potion made with ground up dried newt, sunflower seeds and some CBD. A month later, 95 have recovered completely, 3 are still in hospital but recovering and two have died. I call a press conference and announce that my remedy has a 98% cure rate and should be widely used.

Do you accept my claim? I hope not! As Groucho Marx said when asked “How’s your wife:” “compared to what?” If you have followed this evolving story, the death rate among people with Covid-19 who have symptoms is estimated to be somewhere between 1 and 2%, with a huge variation dependent on age and ethnicity. Young Caucasians have a death rate well under 1% while octogenarians have a mortality well over 10%. Thus, to make any sense about my claimed “cure,” you must first ask for a breakdown of the ages and ethnicities of those I treated. If they were all white college students, chances are my remedy killed rather than cured. If they were all elderly Blacks, there may be something that warrants further study. Finally, no matter what the demographic breakdown, the most important question of all, is how my remedy compared to other available treatments.

This brings up the idea of the controlled clinical trial. There is a well-known aphorism in science: the plural of anecdote is not data. Medicine is full of “accepted” treatments that were proven worthless, and the fact that a patient improved after a treatment does not always mean they recovered because of the treatment. They may have recovered despite the treatment, which actually made some patients worse, or would have recovered with no treatment.

The current gold standard in deciding whether one treatment is better than another is the controlled trial. A large group of patients are randomly given treatment A or B; neither the patients nor the doctors know which they are given. After an appropriate amount of time, the pre-specified outcome is compared between the two groups. The outcome chosen is crucial: ideally, it is both important and clear. I always look first at death rate – whether one is alive is obviously important, and it is also very clear; you don’t need a committee to decide if a patient is alive (as you do in many reported outcomes).

When the trial is reported, the researchers will describe the difference and will usually indicate whether it is “statistically significant,” using a P value. This is simply the odds that the outcome was due to a real difference between the treatments or simply by chance. If you flip a coin and it comes up heads three times in a row, this does not mean the coin is unbalanced. Every time you flip a balanced coin, there is a 50% chance it will be heads, so getting heads three times in a row is not surprising. If you get heads 20 times in a row, you should be suspicious that there is something unusual about the coin. Hence, when a study reports a difference, they indicate the likelihood the account was due to chance. A “P less than .05” simply means that there is less than a 5% chance the difference was due to chance. Note that this is not a guarantee the results were valid.

Also important, and particularly relevant to Covid treatments these days, is whether the results are presented as relative or absolute differences. Drugs companies, not surprisingly, tend to emphasize relative differences, which are usually larger. Let’s say that 40% of patients with a very nasty disease are dead in year without treatment, while with treatment A, 25% die and with treatment B, 22% die. The honest way of presenting this would be to say that 3 out 100 more patients lived with B than A. A marketer would rather say that the death rate was reduced by 12% (22 compared to 25).

The Mayo Covid study had several issues limiting its value for making life-and-death decisions. Most important, the study was observational, not controlled. There was no group given an alternative (or only supportive care). No attempt was made to select who got serum with different amounts of antibody. They followed a large group of patients who were given plasma and compared those who received transfusions within three days of the diagnosis with those transfused four or more days after. They also compared those who received higher, medium or lower amounts of antibody in the plasma they happened to receive.

My focus was on the death rate at 30 days (a “hard” end-point – good). Those transfused earlier had a 21.6% death rate; those who got the plasma later had a 26.7% death rate. Thus, the absolute difference was 5% - possibly important if verified by better studies, but not the “35% reduced death rate” put out to the media. The latter figure came from comparing death rates at 7 days between those who received very high dose of antibodies (8.9%) and those who received very low levels (13.7%), a difference that was less at 30 days. There was no way to prove the groups were the same.

Does convalescent plasma help patients with severe Covid-19 survive? I think the only honest conclusion one can reach is “Maybe.” It is biologically plausible. The observations reported are consistent with a possible benefit, but better designed trials are clearly needed before this can be considered of proven benefit.

What I do know is that the FDA, which is supposed to be our defense against allowing ineffective and/or dangerous medications to be marketed, has increasingly made decisions based on political pressure rather than science.

This goes hand in hand with the Trump administration’s directive to the CDC to change its testing guidelines to discourage testing of asymptomatic Covid contacts, a decision that is opposed by almost every expert in the field. Fewer tests may lead to fewer reported cases but will lead to wider spread and more deaths.

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CBD: salve or snake oil?

Cannabidiol (CBD) products are everywhere, in products ranging from bath salts to dog treats, and touted as remedies for just about every ailment. What are they? Do they do any good? Are they safe?

Cannabis sativa, better known as marijuana, is an annual flowering plant that contains over 100 identified compounds. The best known is tetrahydrocannabinol, or THC, which is responsible for the psychoactive effects of marijuana, the euphoria or “high.” Another well-known component is CBD. Unlike THC, CBD does not make users high, but is promoted to reduce pain, ease anxiety and give better sleep.

Commercial use of CBD has exploded, on-line and through herbal and health-food sales outlets. Sales through these sources in 2018 totaled $52.7 million, over triple the amount sold in 2017, and replaced turmeric as the top-selling product of these companies.

What do we know about its benefits? There is an FDA-approved drug (Epidiole) used to treat two rare seizure disorders in children. Every other promoted use has scant evidence behind it. While there have been hundreds of papers published about CBD, most studies have been small and usually without good research design. Moreover, a study published earlier this year in The Annals of Internal Medicine found that a large majority of the authors of articles promoting CBD use had close ties to the CBD industry, raising obvious questions about conflict of interest.

Is CBD safe? A huge problem is the lack of oversight of what you are getting, since CBD is sold as a “supplement” rather than a medication, thus removing FDA regulation. CannaSafe, a California cannabis testing lab, recently analyzed 20 popular CBD products and found that only three of the twenty contained what their labels claimed. Eight contained less than 20% of the amount of CBD on the label, and two contained none. Some of the products were found to contain high levels of poisonous solvents.

CBD can interfere with the way your body deals with many prescription drugs, so if you are using it and are on any medication, be sure to tell your doctor. It can also adversely affect the liver, even when not tainted.

If you want to use one of these products, be sure they are EPA-certified Organic, as this will lessen the chances of chemical contamination. You might also want to get products from Europe, where they are much more closely regulated.

Does CBD do any good? It is unclear at this time, but probably not. The limited studies done to date by legitimate researchers relate in part to the DEA's insistence that marijuana is a "class I" substance, putting it up there with heroin and methamphetamine, even though alcohol would probably be a better analogy. Some very preliminary studies needed to be expanded.

Is CBD safe? Possibly, given the comments above, but caveat emptor.

Next time, let’s look at THC.

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How to avoid the bite

While lions and tigers and bears (Oh my!) may be fearsome predators, humankind is at much more risk from critters at the other end of the size scale: mosquitos and ticks! World-wide, malaria, carried by anopheles mosquitos, caused 228,000,000 cases and 405,000 deaths in 2018. While malaria has been largely banished in North America, mosquitos also carry the viruses causing Eastern Equine Encephalitis, Zika, West Nile, Dengue and chikungunya: diseases that are serious and often fatal.

Ticks carry Lyme disease, Babesiosis and Rocky Mountain spotted fever among others. Since many of these illnesses have no treatment, prevention is key. Prevention means not getting bitten by mosquitos and ticks. Is this possible? Yes, by using a combination of simple measures: avoidance and deterrence.

Mosquitos tend to be most active feeding between dusk and dawn, so when mosquito-borne illnesses are around, it is wisest to avoid being outdoors at that time. Barbecues at noon are lower risk; barbecues at 7 PM much higher, so have the friends over in the afternoon, not the evening. Drain any pools of free-standing water (where mosquitos breed) – and do not forget such mosquito havens as gutters. Be sure your screens are in good repair and fit snugly. If you use window air conditioners, be sure to seal around them.

Clothing can be protective: do not walk barefoot through the grass, where ticks are lurking and ready to latch on. Wear long pants and long-sleeve shirts when mosquitos are around.

Finally: use effective repellants. The news media recently carried banner stories about a new “natural” insect repellant, nootkatone, found in minute quantities in grapefruit skin and Alaska yellow cedar trees. You had to read the small print to learn that while it has been approved, it will not be commercially available until 2022. Until then, several effective products are widely available.

Best known is DEET (dimethyl-m-toluamide), available in lotions, sprays and wipes. While DEET products can contain from 5% to 99% of the active ingredient, at least 20% is recommended, and concentrations above 50% add little. DEET can cause skin irritation, but is generally very safe, and can be used on children and infants over 3 months.

An alternative product with similar efficacy is picaridin, available in concentrations of 5-20%. 10% is a good compromise and is safe for children.

A slightly less effective product is IR3535. Be careful to get a product that has 20% concentration; the 7.5% product has been found ineffective.

For those inclined to “natural” products, there is oil of lemon eucalyptus (whose products often use the word Botanicals in the name). It is somewhat more likely than the others to cause skin irritation and should not be used on children under 3.

Citronella oil-based products are less effective and are not recommended unless nothing else is available.

Finally, consider use of permethrin on clothing and footwear. It kills mosquitos and ticks on contact. You can spray it on not only clothing, but on tents, sleeping bags and mosquito nets. Permethrin-impregnated clothing is commercially available and remains active for several weeks, though multiple launderings.

While you may see wearables such as wrist bands with insect repellants, none of these are of much benefit.

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Sunscreens: are they harmful?

Ah, summer. Beaches, swimming, sailing, outdoor parties, skin cancer.

Wonderful as it is to be outdoors in the sun, there is a potential price to pay. In addition to the visible sunshine and heat we get from the sun, we also get ultraviolet (UV) rays, that are damaging to our skin. There are at least three forms of UV light: A, B and C. All the UVC rays, with the shortest wavelength and which are the most damaging, are absorbed by earth’s ozone layer, as are many of the UVB rays, but most of the UVA and some of the UVB rays reach us. UVB rays on our skin have the valuable function of producing Vitamin D from precursors, so people who avoid all sun may need to take supplements to avoid becoming deficient in D.

UVA and B cause sunburns and are a major risk factor for melanoma and other skin cancers in fair-skinned populations. Some 60,000 people world-wide die of melanoma every year. Not surprisingly, Australia and New Zealand (with large majority Caucasian residents and a lot of outdoor activities) lead the world in melanoma cases per 100,000 people. Next in line are the Nordic countries – presumably because they are the fairest of the fair-skinned peoples. People of African and South Asian descent are much less susceptible to this risk. Melanin is the body’s protection against UV rays, and dark-skinned individuals have more melanin in their skin.

“Suntan lotions” with little UV protection may allow one to get a tan without as much risk of burning, but they offer almost no protection against skin cancer (nor the cosmetic effects of prolonged sun exposure: wrinkles and leathery skin years later).

Enter sunscreens. These come labelled with SPFs (skin protection factors). This number is an estimate of how much longer you can be in the sun without burning; if you would get a burn after 30 minutes in the sun, then a lotion with an SPF of 6 would let you be in the sun for 3 hours before you burned. Most dermatologists recommend using a lotion with an SPF of at least 30 to prevent skin cancer down the road.

One concern is whether habitual use of sunscreens might lead to Vitamin D deficiency, but this does not appear to happen based on recent research.

There has been a lot of press recently about another potential risk. Sunscreens may include organic and inorganic filters. Inorganic filters such as titanium dioxide and zinc oxide physically reflect UV rays away from the skin and are clearly safe. Organic filters, too many to list, absorb UV radiation and are the most widely used because they are colorless. Two trials conducted by the FDA found that “normal” application of sunscreens led to measurable levels of these compounds in the blood of people who used them. The FDA was careful to point out that this was not a reason to stop using them, but simply a call for more research.

If the news stories have you worried, what should you do? I would strongly recommend you not stop protecting your skin. There is no current evidence that the compounds have any harmful effects and any theoretical worries must be balanced against the known carcinogenic effects of the sun’s UV rays.

One obvious step is to use physical barriers: dark umbrellas block most of the UV rays, as does most clothing: denim, nylon and polyester (but less so cotton). If media reports have you worried about sunblock, use zinc or titanium-based products, which the FDA considers totally safe. If you consider those unsightly, use the organic-based products; their “hazards” are conjecture and their benefits proven.

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