How do you design an experiment?

Big data can make lab-mice studies more relevant to humans - ISRAEL21c

Alzheimer’s research has had some cruel experiences in the last few years. Drugs that seemed so promising with animal models failed when tested on humans. These frustrating outcomes caused the National Institute of Aging to dig deeper to determine why animal models were not translating to human success.

One of the Institute’s projects was AlzPED (Alzheimer’s Disease Preclinical Efficacy Database), not just a database of research papers, but “curated” papers evaluated as to whether the paper includes the factors listed below. As the mission statement states: AlzPED is designed to help identify the critical data, design elements and methodology missing from studies; making them susceptible to misinterpretation, less likely to be reproduced and reducing their translational value.

The categories and comments were added by me, so should be taken with a grain of salt. For the category called “Stats”, keep in mind the importance of statistics to experiment design. The gold standard of experiment design is a “randomized double blind” model. Neither the patient nor the researcher knows whether the patient is receiving the experimental treatment, a standard treatment or a placebo. Patients are assigned randomly to a category. How the researcher assures a random selection and sufficient sample size would be defined in the statistical plan. “Subjects” category refers to test subjects, and “Drug” category refers to the drug or other therapy being tested.

As you scan this list of factors, you can start to see how this level of detail would facilitate translating the animal experiment to a human experiment. How many research papers describe all these factors? Very few. AlzPED’s 2020 analysis of 1,030 papers indicated that only 2% included power/sample size calculation while 95% or greater included drug parameters such as dose, frequency, transport. Of the nine core experimental design elements, a mere 0.2% of reports had all nine. Few research papers reported more than 5 core design elements, and most studies reported only 2-4 core design elements.

So, still much training and development of templates is needed to improve Alzheimer’s research papers so they are more likely to translate from mouse success to human success. These factors look like they are not Alzheimer’s-specific, and could also be used to evaluate Parkinson’s research papers.

Note: You may need to scroll to your left to read the Comments.

FactorsCategoryCoreComments
Conflict of InterestGeneralYFinancial conflicts of researcher (e.g., receives grants from drug company)
Power/Sample Size CalculationStatsYHow many test subjects needed to conclude with, e.g., 95% confidence (power)
Blinded for TreatmentStatsYChosen “blind” – without knowing if in Control group
Blinded for Outcome MeasuresStatsYChosen “blind” – without knowing if in Control group
Randomized into GroupsStatsYRandom selection of Control Group vs Therapy Group
Statistical PlanStats
Inclusion/Exclusion Criteria IncludedSubjectsYExample: Subjects must be 18-80 and diagnosis < 5 years
Study Balanced for SexSubjectsY# of males vs # of females
Genetic BackgroundSubjectsY
Sex as a Biological VariableSubjectsY
Number of Excluded AnimalsSubjects
Number of Premature DeathsSubjects
Age at the Beginning of TreatmentSubjects
Age at the End of TreatmentSubjects
ADME MeasuresDrug Absorption, Distribution, Metabolism and Excretion. ADME studies are designed to investigate how a chemical (e.g. a drug compound) is processed by a living organism
BiomarkersDrugWhat biological measures (e.g., blood, skin, cerebral fluid) are used
Pharmacodynamic MeasuresDrugMeasures of what the drug does to the body
Pharmacokinetic MeasuresDrugMeasures of what the body does to the drug
Toxicology MeasuresDrugLethal dose and other  measures of how toxic the drug is on test subjects
FormulationDrugComposition of drug
DoseDrug
Frequency of AdministrationDrug
Duration of TreatmentDrug
Route of DeliveryDrugHow drug is delivered (e.g., orally, intravenously)

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Little Pharma

Leen Kawas – Oregon Science Startup Forum
Leen Kawas, not your typical image of a Pharma CEO

Where do new drugs come from? Your answer would probably be something like “Big Pharma”. But there’s also “Little Pharmas” out there, often pinning their hopes on one big breakthrough.

One firm in this category is Athira, a Seattle-based company, founded and headed (to my astonishment) by a young woman of color. CEO Leen Kawas, 35, immigrated from Jordan in 2007. While earning her Ph.D. in molecular pharmacology from Washington State University, she founded in 2011 the company that would become Athira. I actually wrote about her work in early 2016.

It takes an astonishing amount of money and time to bring a new drug to market. The drug the company was working on in 2016, and is still working on today, NDX-1017, uses regenerative technology to rebuild connections between neurons. The drug could halt or reverse the nerve damage that causes Alzheimer’s disease and other illnesses including Parkinson’s and ALS, or Lou Gehrig’s Disease.

Fixing the synapses between neurons is a new approach to Alzheimer’s. Other companies’ promising drugs that targeted toxic proteins (amyloids) connected with Alzheimer’s have failed in late-stage trials. Dr. Kawas has enough confidence in the efficacy of Athira’s approach that she was able to raise $85 million in June from venture capitalists, and $204 million in September in an IPO. (See “astonishing amount of money” above.)

What’s all this money for? Athira plans to launch a Phase 2 clinical trial by the end of 2020 and enroll up to 300 people with mild to moderate symptoms of Alzheimer’s disease. Phase 2 goals are drug efficacy and identifying side effects, if any. This would be followed by a larger Phase 3 clinical trial, used to obtain approval for the drug from USFDA.

Let’s hope this drug has some effect on Alzheimer’s (and perhaps Parkinson’s, which has a similar toxic protein model to Alzheimer’s). By 2021, Dr. Kawas will have worked 10 years on this drug – imagine spending a decade on something that ends up not working.

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I voted yesterday

I voted yesterday.

What a powerful sentence that is.

“I” – It’s the 100th anniversary of women’s suffrage in the US and I am grateful to all my unknown sisters and aunts and grandmothers who battled for my right to vote. That’s why I vote every time — I can’t let them down. I am also grateful as a person with Parkinson’s that I don’t have to stand in any lines to vote. I suppose I could stand for an hour, but I really don’t want to test my limits.

“voted” – It took me about an hour to vote. There were several county charter amendments I needed to check on the Internet. I always have to research the judicial races. I needed more than the Voter’s Guide to learn one of the judicial candidates had…just passed the Bar! I am allowed the essential luxury of deliberate, methodical contemplation of ballot choices because I vote by mail. I haven’t set foot in a polling place for at least 20 years. First I was a “permanent absentee”, then King County switched to mail elections; now the whole state is all-mail. Kudos to Kim Wyman, whom I enthusiastically voted for her third term as Secretary of State. She has done an excellent job of defending and strengthening Washington State’s all-mail electoral process – and oh yes, she’s a Republican.

“yesterday” – I actually filled out the ballot on Sunday, but I delivered it to the ballot dropbox yesterday, Monday, October 19. We received our ballots in the mail late last week, and because of our all-mail system, we have the luxury of completing the steps of the election process at our convenience over a 3-week period. The dropbox is within walking distance and is a permanent structure (think like a Goodwill dropbox), one of dozens in King County. I think I’m safe to say that all 39 Washington counties have at least one dropbox. I checked and even the least populous county (Garfield with 2300 residents) has one. I am aghast at Texas, where the Republican governor limited drop boxes to one per county (“to combat voter fraud”, he apparently claimed with a straight face). The first court overturned this obvious voter repression move, but the appeals court (populated with Trump appointees) allowed it.

I have no qualms about the security of my ballot and feel confident it will be accurately counted. I hope the same for your ballot. And it bears repeating; the only ballot that ultimately doesn’t count is the one that you don’t vote.

YouTube extra: Let’s pump out a patriotic march: Stars and Stripes Forever played by the Marine Band. Love the uniforms and the piccolo quartet! If you have to wait in a line to vote, turn this on as you march into that polling place.

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The New Normal

Does “Golden Key” actually solve encryption issues? | Kaspersky official  blog
Secret Golden Posture Key

Welcome to the New Normal. You’ve been seeing this phrase a lot — describing how life has been turned upside down by the pandemic; masks, isolation, working from home have made this time anything but normal. We know in our heart of hearts that when we get back to “Normal”, it will never be the same as before.

You’ve also seen this phrase for climate change. Forest-chomping wildfires, hurricanes that make insurance executives reach for the antacids, biblical droughts — all the “New Normal”. There is no “Normal” we can go back to.

And then I have my own personal “New Normal”. I will have to be aware of where my body is in space, as I am sitting, standing, walking …I will have to be aware of my body’s position ALL THE TIME.

A couple people have asked how my “Physical Therapy Boot Camp” went. This is the LSVT-BIG program, a specialized PT program for Parkies, using repetition and the brain’s neuroplasticity to build new muscle memory. It’s an hour a day with a physical or occupational therapist, four days a week for four weeks. There is a standard suite of exercises with an emphasis on definite and big movements. (Parkies tend to get bradykinesia – slow, small movements like foot scuffing). The therapists also develop functional exercises for activities you may find difficult, e.g., getting out of a car.

Some positive outcomes:
–The pain in my right lower back is no longer continual. I can go for long stretches before my back starts hurting again.
–I’m much more aware of my body’s position.
–I have a new set of exercises. Doing them takes about 20 minutes and I feel better and straighter after I’m through.
–I’ve also picked up exercises specifically aimed at building up the hamstrings (back of thigh) and the butt cheeks. I need these muscles for walking and keeping myself upright.

But I don’t feel like I’ve really acquired sufficient new tools to correct my posture. When I’m sitting, I am struggling not to get sucked to the left and not to press down on my left toes with my left heel raised (a peculiar move I’ve just started to do). My most ardent wish is to participate in a Zoom call and sit still and upright like a normal person. Instead, I tend to bob in and out of the frame, as I try to correct myself.

When I’m standing, I’m getting better at moving torso to right (and hips to left) to straighten my posture. But it’s still hell to do things like fold laundry, do kitchen prep, brush my teeth — once you start thinking of something else, the posture form tends to vanish.

I’m still mystified how to walk, despite spending a good chunk of the LSVT sessions on walking. Only at the very end of the LSVT sessions did I get the assignment to align my body (I use a piece of tape down the mirror as my guide) then try to move, staying within this position. Even for normal people, this is dang near impossible to not have your head and torso bob to the left and right of an imaginary centerline, once you start moving. Fortunately, I have a couple followup appointments so I can review this area (yet again).

I think my expectations of LSVT BIG were somewhat unrealistic. I admit that I nursed what I recognized to be a fantasy that I would be taught the Secret Golden Posture Key — and poof! — my spine would pop into place, beautifully aligned. The therapists did point out that I have had this tippy posture for at least 3 years, and building a new muscle memory will take thousands of iterations of correct posture – hence my “new normal” of constantly correcting posture.

There is one accomplishment from the LSVAT sessions that I’m really proud of: I parked for 16 appointments in the ghastly-tight-concrete-pillars-every-car-is-a-SUV-every-space-is-marked-“compact” Virginia Mason Hospital garages – and did not dent or scratch my car!

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Get your flu shot!

Flu shot facts & side effects | Live Science

Simple way to fight COVID? Get your flu shot.

Jane Brody, the wonderful longtime science writer at the New York Times does a better job than I would explaining the importance of this year’s flu shot. She is my main source for this post. The big reason for getting the flu vaccine is to reduce the stress on our already stretched health care system. The more people get the flu shot, the more herd immunity becomes a possibility. Last year, incredibly, only 45% of US adults got the flu shot.

Let’s deal with the excuses and false statements —

“I don’t have time” — Really? You don’t have 15 minutes for a shot but you’ve got a week to be miserable with the flu?

“I don’t know where I’d get a shot” —
You don’t have to go to your doctor or a hospital. Nearly every drug store and major grocery chain is offering flu shots. My local town is offering a drive-through immunization clinic.

“I got a flu shot once and caught the flu from it” —
Repeat after me: you cannot get flu from a flu shot. It’s made with a inactivated (that means dead) virus.

“I don’t believe in vaccines. It’s more natural to just get the flu.” —
Saying this is kind of like saying “I don’t believe in gravity.” Vaccines are a proven safe scientific concept that have been around since at least the ancient Chinese in 1000. Sure you can “naturally” get infected with the misery that is the flu, but then you will be an infection vector for all those around you, including those with compromised immune systems. Do you really want to risk infecting Granny and the new baby?

“Don’t need a flu shot. I’m really healthy, workout every day, and I take lots of vitamins.” — Congratulations on your healthy lifestyle. But you can still get the flu and spread it to….yep, Granny and the new baby.

“Don’t need a flu shot. I got one last year.” —
Nope, gotta get a flu shot every year because those pesky viruses mutate. Also, immunity tends to weaken after a year.

“Flu shots don’t work.” —
Vaccine effectiveness averages around 50%. Doesn’t sound very impressive, does it? But if you do get infected with a mutant flu strain that wasn’t covered by this year’s vaccine, your flu should be less severe. By the way, researchers will be dancing in the streets if they can make a Covid vaccine with 50% effectiveness.

“Hey, it’s only the flu.”
Influenza is not as nasty as Covid-19, but it’s still nasty. Just like Covid, people can die from the flu. CDC estimates that influenza was associated with more than 35.5 million illnesses, more than 16.5 million medical visits, 490,600 hospitalizations, and 34,200 deaths during the 2018–2019 influenza season.

I’m scared of needles.” —
Hey, I’m not fond of them either. But I have a nice conversation with the person giving me a shot and then “OUCH!” it’s all over. C’mon, Man up. You can do this.

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Report from Boot Camp

On September 8, I started what I’m calling “PT Boot Camp” in a concentrated effort to get rid of my tippy posture. I have been fighting this leaning posture since at least 2017. (See photos.) Posture issues are not uncommon among Parkies; mine even has a real medical name – my neurologist refers to it as the “Pisa Syndrome” (get it?). I no longer have a mental image of what is “straight”. In both of these pictures, I thought I was standing up straight.

The “Boot Camp” is the LSVT BIG program, an hour a day, 4 days a week for 4 weeks, plus homework. What is LSVT BIG? The acronym has become somewhat meaningless. It stands for Lee Silverman Vocal Training. Lee Silverman was not the inventor of the technique, but rather the first patient. And the reference to vocal training refers to the original program (LSVT LOUD) for increasing the volume of soft Parkinson’s voices. Both movement and voices tend to get smaller (“bradykinesia”) for Parkies.

LSVT BIG consists of a standard set of exercises, plus the therapist develops customized exercises to address specific tasks that you identify as your problem areas. In my case, standing up straight is the biggie, with some others like standing at the kitchen counter doing meal prep, rolling over in bed, getting out of a car, etc.

I am now through the first week, and do the exercises twice a day. (I suspect I will get a few more exercises.) The rationale for the constant repetition over four weeks is to take advantage of the brain’s neuroplasticity to create new movement patterns. The exercises are deceptively simple although I still have to consult the cheat sheet to do the exercises. There is an emphasis on what I would call “cheerleading” the exercises – shouting out the count, doing them with a lot of energy, using, well, BIG movements.

What’s the results? Back seems generally less painful. However, as I type this, despite my best efforts, I am constantly being tugged to the left as if by a powerful whirlpool. The biggest impacts so far have been to my wrist (from clenching the steering wheel as I drive the 25-mile round trip to the clinic every day) and my wallet ($40 copay each day – ouch). But, kvetching aside, I am hopeful this program will help make a difference in my posture.

YouTube extra: Might as well get warmed up for cheerleading my exercises by watching the 24-time national champions, the University of Kentucky Wildcats. Here they are in 2019.

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The search for the Holy Grail continues

“I have not failed. I’ve just found 10,000 ways that won’t work.” 
Thomas Edison on inventing the light bulb

Much has been written about testing for the COVID-19 virus. One test is fast but produces a lot of false negatives. Another test is more accurate but takes two weeks to get results. But at least there is something (the virus itself or the presence of antibodies) to test for. In the case of Parkinson’s disease, there is nothing to test for to measure the presence and progress of the disease. The Holy Grail of Parkinson’s research is a search for a biomarker.

Given this Holy Grail, it was a disappointment to read an article headlined “Alpha-Synuclein…Not Valid Biomarker…..”. Parkinson’s is caused by clumps of alpha-synuclein proteins interfering with the neuron’s recycling process, causing the neuron’s death. Logically, the presence of alpha-synuclein in some sort of tissue or bodily fluid should indicate Parkinson’s- right?

Wrong. Too many false negatives (test says you don’t have PD when you actually do) and false positives (test says you have PD when you don’t.)

Here are results from the Systemic Synuclein Sampling Study , an initiative from The Michael J. Fox Foundation. A total of 59 patients with idiopathic Parkinson’s disease and without dementia were enrolled at six U.S. sites from October 2015 to August 2017. For controls, 21 healthy individuals were also included. 

Blood : No significant difference in alpha-synuclein levels between healthy controls and Parkies.

Saliva: No significant difference in alpha-synuclein levels between healthy controls and Parkies.

Cerebrospinal fluid (CSF) (This is the fluid cushioning your spine and brain.)\: The good news is that alpha-synuclein measurement in CSF correctly identified 87% of the Parkinson’s cohort. The bad news it also identified some 40% of the controls as having Parkinson’s.

Skin tissue: Opposite of CSF. Only one healthy control had test results that were a false positive, but only 24% of Parkies were correctly identified.

Submandibular gland tissue (This is the area below your tongue and yes, it sounds excruiciating to scrape a tissue sample from there!): Again, only one healthy control had a false positive, but only 56% of Parkies were correctly identified.

So…back to the laboratory. The research team believes that measuring toxic alpha-synuclein clumps rather than all forms of alpha-synuclein may provide a better biomarker for the disease. The analogy might be that these inaccurate tests were detecting oats when you really needed to detect oatmeal. Researchers can detect alpha-synuclein clumps right now. They’re called Lewy Bodies. Unfortunately, you have to be dead – they’re only visible in an autopsy. But if there were a way to detect these while the patient is still alive….??? The search for the Holy Grail continues.

YouTube extra: Relive your wasted youth rewatching scenes from Monty Python and the Holy Grail.

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The Vaccine Horse Race

Right now, there is a desperate horse race going on to develop a vaccine for COVID-19. The New York Times has confirmed that at least 88 candidates are under active preclinical investigation in laboratories across the world, with 67 of them slated to begin clinical trials before the end of 2021. From the New York Times, here’s the horse race as of 8/31/20:

Do you wonder what all that “Phase 1”, “Phase 3” testing is all about? Do you wonder why vaccine development is taking so long? If, as President Trump so ardently wishes, a vaccine magically came out, say, on October 30, 2020, would you have confidence in taking it? This is a good time to review the drug testing process.

The different phases of testing are from the USFDA (Food and Drug Administration). Other countries presumably have similar testing phases. Before any testing on humans, there is usually animal testing. There has been animal testing for COVID-19 vaccines; animal testing for Parkinson’s drugs is problematic because only humans get Parkinson’s — it has to be simulated for animal testing.

Here are the drug testing phases for human testing:

Phase 1 – Safety — Typically a small (15-100) number of testers, who usually are healthy, without the disease the drug is directed against. The goals of this phase are to identify side effects and their severity, and the appropriate dosage. This can take several months to a year or more.

Phase 2 — Efficacy — This is a much larger test, which usually includes both healthy controls and people with the disease. The magic phrase here is “randomized trial”. This is considered the “gold standard” of testing: A tester may randomly get the drug or a placebo; neither tester nor researcher are able to identify which one. Duration can vary from months to years – obviously a test that was less than, say, 6 months would not give very complete information.

Phase 3 — Further clinical testing — The number of testers is expanded (from perhaps several hundred in Phase 2 to several thousand in Phase 3). Testing continues to be randomized and blind. This phase provides more information on the full range of side effects and efficacy on different patient types (e.g., vary by age, vary by obesity). After this phase, the pharmaceutical company applies for FDA approval.

Phase 4 — Post-market studies — There may be studies after FDA approval. For instance, the drug may be tested for long-term effectiveness or efficacy versus newer therapies.

When you see the objectives of each phase, you can appreciate why drug testing takes so long. Just recruiting testers takes a lot of time. The Michael J. Fox Foundation has tackled this area for Parkinson’s testing. Sign up for the Fox Trial Finder right now. Already signed up? Check to see if there’s any suitable testing opportunities.

Vaccine developers are trying to speed this testing process along as much as possible, but that vaccine that (watch for it) will magically come out on October 30? Hmmm….think I’ll wait for a bit more testing.

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Laura goes to summer camp

j just returned from a splendid summer trip to Eastern Oregon. which felt like going to summer camp. This is the trip where I was going to backpack in the beautiful Eagle Cap Wilderness, but after a trial backpack, quickly decided that I just didn’t have the physical moxie to do a backpack. I am indebted to friend and fellow Parkie Bloggie Carol Clupny who suggested a way to salvage the trip — Our spouses, both eager to do a Real Backpack, would go on the 3-night backpack while Carol and I hung out and day hiked in the Wallowa Lake area.

Spectacular views from Mt.Howard-a tramway does all the heavy lifting- some 4000 feet from Wallowa Lake (in the background) to the top.
Carol’s recumbent e-trike was the hit of the RV park, especially among the younger set. Carol has ridden her tandem bike with her husband in the RAGBRAI (ride across Iowa) 4 times!!

The summer camp started with a visit to Minam River Lodge, a totally rebuilt lodge grandfathered into the middle of the Eagle Cap Wilderness. You can only access the lodge by an 8.5 mile hike or fly in. With Paul carrying most of my clothes and snacks, I was able to make the hike, but I did trip over a rock cleverly camouflaged with trail dust. I was fine but got this attractive black eye.

“Ya shoulda seen the other guy….!”

Ahh…three days of gourmet cuisine and fluffy mattresses in the wilderness. My kind of roughing it. The trail out was uphill, so I decided to use the deposit I had already paid for the aborted backpack trip to instead carry me. Three hours in the saddle was – ah – felt in certain parts of my anatomy the next day. I required help from the wranglers getting on and getting off but I made it .

Yee Haw!

YouTube extra: How can I resist? Patsy Montana singing and yodeling “I want to be a Cowboy’s Sweetheart.” I think I prefer the straight song, but I’m also throwing in the more “Hollywood” version. Either way, she was the first female country singer to have a gold record ( a million sales) – Yee haw!

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Blog Lessons

I was recently asked about starting a blog, which caused me to reflect on what I’ve learned from writing this blog since my diagnosis in 2012. I also thought I should review why I started the blog. Is that still why I write?

–First, some humility. When I started “The Magic Trick – Life with Parkinson’s”, I thought I was being soooo trendy and unique – and that I had come up with a unique title. Nah. Turns out everyone’s second cousin starts a blog. And that title? If you Google “magic trick Parkinsons”, you will indeed get my blog but you’ll also get the distinguished fellow in the photo, Sir Michael Parkinson, interviewing a magician. Sir Michael is a British TV interviewer.

–I wondered if I had written more than 100 posts yet. Wow – turns out this is my 203rd published post (since 2012). I do not have the discipline, energy, or time to write every day, or even on a regular basis. I generally get in 1 or 2 posts a month

–My English teacher mother was right: Proofread, proofread, proofread. I cringe at the typos and errors I find in past posts. And my adman dad was also right: He told me whenever you write something and think “how cute! how clever!”….you’d better leave it out.

–Why did I start the blog? I wanted to report on Parkinson’s research, explain the neurological vocabulary, and keep family and friends apprised of my status. Turns out the most important reason for the blog is my own mental health. I feel like I have a bit more control over this wacky disease when I can organize my thoughts in a post.

–I also try very hard to be positive. No one wants to read a dreary complaint.

–Do I have any readers? Yes! Not very many, but I do have thousands of views (well, 2000 or so) each year. I have readers across the English-speaking globe, including Tasmania, Canada, and Miami. I even visited a reader in London. And it’s very satisfying for my ego that I get comments within minutes of publishing.

–But ultimately I’m doing this blog for myself. I enjoy the writing and I think it’s good for my mental health. And I love picking out the YouTube extra!

–Biggest surprise? Many people have commented how humorous the blog is! Gee, I never intended to be funny….

YouTube extra: Yes, of course Sir Michael Parkinson interviewed Sir Michael Caine. And I’ll throw in the theme from Alfie, one of Michael Caine’s earliest (1966) movies. Ah, Burt Bacharach….don’t compose ’em like that any more.

Posted in Parkinson's Basics, Parkinson's People, Status | Tagged , , | 4 Comments