Bad Blood. A review.

My blog, The Weekly Packet, (https://theweeklypacket.com/category/health-care/ ) of April 30, 2016 ran under the title “The Theranos evidence, waiting for a story.”

In the text, I said, “… looking at the facts is like looking at individual organs at an autopsy, after the diener has washed them, weighed them, and put them in clean pans. What we need now is the pathologist to come in, and with knowledge and experience, he or she will tell the story that puts the facts together into a coherent narrative. At some point, the narrative may well make an instructive case study.”

John Carreyrou’s new book, Bad Blood: Secrets and Lies in a Silicon Valley Startup, tells the story with spellbinding skill and detail. Those of us who had some background, however minimal, in laboratory work knew that Theranos had almost certainly over-promised and under-delivered. None of us knew the details.

Carreyrou’s reporting reveals the astonishing extent of the process in a marvelously “coherent narrative.” He details the scope of the deceptions involved, including misleading deals with Walgreen’s, Safeway and even an attempt to involve the army, the vast sums of money lost, and the lives disrupted.

First, no spoilers. Read the book! Then, after the mesmerizing read comes the hard part: what can we learn from this story?

One obvious lesson relates to corporate culture. A corporate culture that encourages tough questioning across disciplines and insists on facts may sometimes seem harsh. In such an environment, though, mutual respect and civility make the system work. What we see in Bad Blood, though, is the destructive effect of siloing and secrecy. And we see that destructive process emanating from the top levels of management.

There’s another lesson, too. A very old one. Making the error of hubris provokes the outcome of nemesis. David Ronfeldt explained in his excellent essay for the Rand Corporation, “Beware the Hubris-Nemesis Complex: A Concept for Leadership Analysis.”

“In Greek literature, hubris often afflicted rulers and conquerors who, though endowed with great leadership abilities, abused their power and authority and challenged the divine balance of nature to gratify their own vanity and ambition. Thus hubris was no common evil: It led people to presume that they were above ordinary laws…”

He continued on,

“Hubris above all is what attracted Nemesis, who then retaliated to humiliate and destroy the pretender, often through terror and devastation. Thus she [Nemesis] was an agent of destruction. The battle won, she did not turn to constructive tasks of renewal and redemption—that was for others to do. Yet her behavior was never a matter of pure angry revenge. There were high, righteous purposes behind her acts, for she intervened in human affairs primarily to restore equilibrium when it was badly disturbed, usually by figures who attained excessive power and prosperity.”

With Bad Blood, John Carreyrou has written not just a stunning piece of non-fiction reporting, but a cautionary tale for our times.

What you see is what there is…

bfb-1-of-1

One of my medical school classmates recently posted a Washington Post article on Doximity, a “social media” site for physicians. The article caught my attention. I think it’s worthy of some comment. The author of the Post article is a brilliant young physician, Dhruv Khullar; his subject was a recent paper in JAMA by Denson, Jensen, Saag, et al. titled “Association Between End-of-Rotation Resident Transition in Care and Mortality Among Hospitalized Patients.” 

The primary finding from this large, retrospective, multicenter observational study was, “end-of-rotation house staff transition in care was associated with significantly higher in-hospital mortality.” The headline for the Post article was “When a new team takes over your care at the hospital, it can be a precarious time.” The change in titles itself is a pretty dangerous transition.

After 14 paragraphs describing the intellectual and emotional uncertainties inherent in teaching-hospital house staff transitions, Khullar finally wrote, “Patients who remain hospitalized during transitions may simply be sicker.” An editorial raising this issue, and the data in the JAMA publication from a restricted analysis that showed markedly lower mortality after attempting to adjust for the degree of illness, at last got some attention in the text.

Here’s my point. There is a critical feature that links all three pieces: the research paper, the editorial, and the Post article; they all acknowledge that the basic premise of the work is flawed, but all three then go on to propose solutions to the  undefined “transition problem” anyway.

Why do I suggest that the analysis is flawed? I’m not a statistician, but after decades of reviewing medical papers, I know enough to realize that this retrospective study was not a statistical problem of tossing fair dice. Patients who are or are not candidates for discharge from hospital on any given day differ in many ways. The study population was not randomized, and as the researchers commented, “the differences observed in patient populations might represent a direct consequence of clinical decisions made because of an upcoming transition rather than confounding. That is, if clinicians try to discharge as many patients as possible prior to transitioning off service, but have more difficulty discharging complex and long-stay patients, the average severity or complexity of patients exposed to transitions in care could be increased.”  [Italics mine]

An ad hoc attempt to adjust for these issues with an alternative approach to analysis demonstrated that the findings were highly dependent on unmeasured factors. As the researchers noted, “The increased 30-day and 90-day mortality risks observed in the main analysis suggest that the delayed discharge of these complicated patients following transition could be detrimental…   The alternative analysis, however, did not demonstrate these findings, [italics mine] which could be related to the noted differences between analyses.”

So, I would like to pose a really interesting question. Why did the authors (and the reviewers and editors) of all three pieces perceive a problem and then propose solutions to it in spite of the facts that the “adjusted” data suggested that the effect of house staff transition was not nearly as great as initially suspected, and that both the authors and the editorialists realized that, “Patients who remain hospitalized during a change in personnel on the inpatient service are likely different than (sic) those who are discharged”?

For the answer, I suggest we ask Nobel Prize winner, Daniel Kahneman. In his book, Thinking, Fast and Slow, Kahneman pointed out, “even compelling causal statistics will not change long-held beliefs…” In the transition-of-care publications authors, reviewers, and editors cling to the long-held belief that doctors can somehow overpower the poor prognosis of old age, frailty, and severe disease by improving the mechanics of healthcare delivery.

In our society, this belief encourages us to think about developing better hand-off forms for interns and residents instead of thinking about how we might really care for patients.

All’s not lost! These observational data do suggest a testable hypothesis. With an upcoming transition in care, rather than pushing early discharge for patients who are basically going to do well, a more productive approach might be to focus effort on recognizing the sicker patients and making appropriate arrangements for them, for example, earlier initiation of specialty consultations, social services for discharge planning, or consideration of hospice or palliative care transfers. In other words, one could randomize two large groups to either usual care (perhaps with the undeniably attractive hand-off forms) or pre-transition intervention starting a week or so before transitions and focused on appropriate discharge planning for sicker patients.

But then again, shouldn’t that be happening now?

P.S. The bird pictured is a blue-footed booby that Katherine photographed in the Galápagos Islands. I included it to make the point that blue-footed boobies do, indeed, have blue feet. This is directly related to the clinical concept that sicker patients do, indeed, do worse.

London in the 1850s

lion-1-of-1

“It was estimated that in 1839, for every person who died of old age or violence in London, eight died of disease caused by poor sanitation practices.”

London began as a Roman town in about 50 AD. By the mid-1800s, the city had become “a Victorian metropolis trying to make do with an Elizabethan public infrastructure.” Thus opens Steven Johnson’s spell-binding non-fiction book, The Ghost Map.

The Ghost Map chronicles the London cholera outbreak of 1854, and central to the story, John Snow and Henry Whitehead’s demonstration that cholera was a water-born epidemic and that the likely source of contamination of the Broad Street pump was a nearby cesspool.

The train of thought establishing the relevance of this 150 year-old story to drug prices today may seem a little erratic at first, but bear with me. As readers of The Weekly Packet know, the evidence supporting pharmaceutical pricing as an important driver of the overall increase in the cost of healthcare in the US is shaky.  On the other hand, the February, 2017 issue of Nature Reviews Drug Discovery has an opinion piece on immune-oncology that shows the huge growth of pharmaceutical research in that discipline. When they come to market, these drugs will not be inexpensive generics, and their prices will reflect the relatively limited numbers of patients for who they are appropriate.

Now, take a look at the facts on the World Health Organization website:

  •  2.4 billion people still do not have basic sanitation facilities such as toilets or latrines.
  • Of these, 946 million still defecate in the open, for example in street gutters, behind bushes or into open bodies of water.
  • The proportion of people practising open defecation globally has fallen almost by half, from 24%to 13%.
  • At least 10% of the world’s population is thought to consume food irrigated by wastewater.
  • Poor sanitation is linked to transmission of diseases such as cholera, diarrhoea, dysentery, hepatitis A, typhoid and polio.
  • Inadequate sanitation is estimated to cause 280 000 diarrhoeal deaths annually and is a major factor in several neglected tropical diseases, including intestinal worms, schistosomiasis, and trachoma. Poor sanitation also contributes to malnutrition.

In addition, WHO says, “The situation of the urban poor poses a growing challenge as they live increasingly in mega cities where sewerage is precarious or non-existent and space for toilets and removal of waste is at a premium. Inequalities in access are compounded when sewage removed from wealthier households is discharged into storm drains, waterways or landfills, polluting poor residential areas.” Sounds like London 150 years ago, doesn’t it?

Here’s how these stories are related. In terms of overall human health, and in environmental quality, the return for dollars spent on sanitation infrastructure is far greater that the return on immuno-oncology. What we are seeing here is that not only has our own US society become divided along economic lines, but our global society has as well.

OK, that’s not exactly “new news.” (I promised that Packet would focus on well-seasoned news.) But here’s a thought. The pharmaceutical industry has a serious problem with its public image. What if, just what if, the industry as a whole agreed to major reductions in direct-to-consumer advertising, focused ads on R&D, and took the lead in supporting improved public health and sanitation infrastructure? What if?

Long-term, it could be a great investment.

(PS: I photographed this mosaic in 2012 at an archaeological site in Greece. It’s not far from the famous ancient latrine often pictured on websites, but much more attractive.)

Two Books well worth the time

For any readers who expected a long essay on Chile, this is not it. Instead, as a sort of preamble to Chile, I want to tell you about the two books that served as much of my “airplane reading.”

I found both books, Genentech, The Beginings of Biotech by Sally Smith Hughes and Science Lessons, What the Business of Biotech Taught Me About Management by Gordon Binder and Philip Bashe, as part of my homework for my own non-fiction book on the rise and fall of Scios and Natrecor. They are both university press publications, from the University of Chicago Press and Harvard Business Press, respectively. That, of course, explains why they weren’t on the tables at the front of your local bookstore when you came in to browse.

Does anyone else still do that? My favorite Ann Arbor bookstore is  Nicola’s Books, and I drop in whenever I’m in the neighborhood. Anyway, back to the topic at hand.

The title pretty well explains the subject of Genentech. Hughes does not spare scientific detail, but she writes about it deftly, blending into the narrative. Readers with even the most basic understanding of genetics will hardly notice that they have gotten a short lesson on recombinant technology along with a great story. Some of you may know that Gordon Binder is a former CEO of Amgen; he focuses primarily on the financial growth of the company. Again, the story is so well told that it carries the weight of venture capital financing, cash burn, and initial public offering strategies without a whimper.

With both of these books, I found myself re-experiencing the excitement of my first undergraduate biology course. The Watson-Crick model of DNA was still new science. The whole world of biology had taken on new shape and meaning, and the individuals who started these companies blended science and business in a totally new way.

I loved David McCullough’s The Wright Brothers; these two books capture the same spirit of innovation in a discipline that has been part of our (at least, my) professional life.

Here’s another highly recommended example of outstanding non-fiction writing: Peter Moore’s  The Weather Experiment: The Pioneers Who Sought to See the Future.    

Why is this post on The Weekly Packet devoted to recommending three obscure non-fiction books? (The Wright Brothers is a best-seller; I’m not counting it.)  First, I can’t imagine writing about politics. Second, it’s still too cold to fish. Third, I wanted to slip in just a teeny plug for the nesiritide book because I just finished a second draft.

Stay tuned.