Modeling coronavirus pandemic

Charting the Next Pandemic
Modeling Infectious Disease Spreading in the Data Science Age

This book was published last year and is a reference for pandemic modeling and in one chapter says:

In the case of coronaviruses, we selected scenarios referring to a case with a transmission rate and natural history of the disease similar to the SARS virus. Thus we assume that the infectiousness of individuals starts only after the onset of clinical symptoms, and we consider the absence of asymptomatic infections. Although we take into account a relatively high reproduction number R0=2.7, the absence of asymptomatic transmission makes all containment measures based on the timely isolation of cases viable and very effective. We therefore consider, for each possible initial condition of the outbreak, two scenarios with a transmissibility reduction, due to prompt case isolation, of 30% and 50% after the first 4 weeks and 50% and 90% after the seventh week, respectively.
Contrary to influenza, we do not consider seasonal variations because seasonal forcing does not appear to have a large impact on SARS. For this reason, we consider only one starting date during the calendar year for each geographical location. In total we provide six scenarios summarized in the infographic charts. The typical coronavirus chart layout and the “how to read it” guide can be found on the following pages.

STARTING CONDITIONS
• R0 = 2.7
• Starting date: varies by geographical location
SCENARIOS
Reduction of transmissibility:
• 30% after 4 weeks; 50% after 7 weeks
• 50% after 4 weeks, 90% after 7 weeks
Origin:
Barcelona, Spain
15 million
passengers/year
Guangzhou, China
Jeddah,
Saudi Arabia
21 million
passengers/year

You may find a recent example of its application in this Science article.
There is only one minor thing that the model can't consider. It is the politicans' and citizens decisions:

Different strategies in a globalized world are the seed of caos beyond the pandemic. Nowadays, this is the current situation. However, as this blogs explains:

There is not a single “one-size-fits-all” approach that allows to respond effectively to the ongoing and rapidly evolving situation. Each country needs to tailor its response in accordance with the capacities of its health systems, its economic resources and infrastructure, and the degree of collective and individual responsibility and compliance with recommendations issued by the authorities. The next generation of health professionals will look back at the different responses to COVID-19 described above and hopefully draw lessons for future infectious disease epidemics.

Meanwhile modeling provides little help.

To test or not to test (for coronavirus)

A Framework for Comprehensive Assessment of the Value of Diagnostic Test

The Value of Diagnostic Information A comprehensive concept of “Value” for diagnostics

A framework to understand value of lab tests is the following one:

Key principles:

• Apply broad array of patient centric value drivers from various perspectives (Comprehensiveness principle)
• Utilize appropriate range of available evidence, reflecting test type and potential risks-benefits (Evidentiary principle)
• Consider reporting direct and indirect costs incurred and avoided over timeframe appropriate for the test (Cost principle)
• Account for immediate and longer-term test impact and patient benefits in representative patient populations (Specificity principle)
• Include quantified estimates as well as qualitative analyses as appropriate (Flexibility principle)
• Incorporate multiple stakeholders’ perspectives (Engagement principle)
• Disclose why the assessment was initiated, who was involved, its purpose, and the decision-making process (Transparency principle)
• Update assessments regularly to keep up with the rapid technological and clinical changes (Relevancy principles)

 Value drivers can come from four major sources:

• Clinical impact: clinical utility and health outcomes associated with the diagnostic technology. The test needs to measure accurately and reliably the analyte/biomarker of interest (analytical validity); detect, predict the outcomes of interest in a patient population (clinical validity) and inform an appropriate clinical decision (clinical utility). Improved patient safety, tolerability, compliance and physical and psychological wellbeing shall be also taken into account.
• Non clinical patient impact breaks down to patient experience, and patient economics, such as proximity of test delivery, reduced follow-up visits, repeat procedures, improved care plan compliance and reduced burden on care givers.
• Care delivery revenue, and cost impact mostly refer to quality of care metrics and more efficient resource utilization (e.g. readmissions; follow-ups, length of stay, wait times)
• Public and population impact refer to macro implications mainly from population health, burden of disease, patient and caregiver productivity perspectives

AdvaMedDx’s Approach for Effective Value Assessment

Source: A Framework for Comprehensive Assessment of the Value of Diagnostic Tests, AdvaMed, 2017

And clinical impact depends on analytical validity, clinical validity, clinical utility, patient safety and patient response. If you have only one strategy for all the patients, like social distancing in the case of coronavirus, then the information post-test will not change the therapeutic strategy. If the test tries to prevent contagion when social distancing can't be applied (health professionals, politicians, journalists, executives, essential services), than you have to test them if there are symptoms. If the test will add information to existing comorbidities to differentiate from other symptoms, then it makes sense. Therefore, this is the current situation in my country. Test, test, test when it adds value.

Climate change and health

Enviromedics: The Impact of Climate Change on Human Health

These are tough times for the relationship between mankind and the planet. Therefore, this is a good reason to know better the relationship between climate change and health. In this book you'll find the details on each topic.
These are the key issues:

Part I. Climate Change Cascade
2 Climate Change 101: A Primer
3 Heat Waves and Heat Stress
4 Extreme Weather
5 Vector-Borne Diseases
6 Mental Health
Part II. Clear and Present Pathogens
7 Air Degradation
8 Water Security
9 Food Security
10 Allergens
11 Harmful Algal Blooms 

 Many of these modern sources of environmental hazards share a common feature—they derive from human activity as much as or more than from nonhuman sources. Radiation exists in nature, but its concentrated forms on Earth are created by humans. Industries produce the goods that support modern life, while they spin off by-products that can harm the environment and humans. We celebrate the productivity of modern agriculture, but if the runoff of pesticides and antibiotics pollutes the water supply and encourages antimicrobial resistance, we pay a higher price than we realize for food.

Balancing this tradeoff is complicated by the fact that the individuals and interests who typically stand to benefit from a polluting activity are not the same as the ones who will suffer the adverse health and other consequences.

Global externalities and how to fix them. This is one of the greatest challenges nowadays.

A controversial view on confidence with medicine

Medical Nihilism

On Therapeutical  Nihilism and effectiveness (Ch. 11), a philosophical view:

The confidence that a medical intervention is effective ought to be low, even when presented with evidence for that intervention’s effectiveness. How low? I do not think that there can be a precise or general answer. It is enough to say: lower, often much lower, than our confidence on average now appears to be. There is surprisingly little direct study of the confidence that physicians or patients or policy-makers have regarding the effectiveness of medical interventions. However, the confidence typically
placed in medical interventions can be gauged by the resources dedicated to developing, marketing, and consuming such interventions.

What explains the disparity between the confidence placed in medical interventions and the lower confidence that I have argued we ought to have? The ingenious techniques that companies use to market their products—paying celebrities to publicly praise their products, funding consumer advocacy groups, sponsoring medical conferences,  influencing medical education, direct-to-consumer advertising—have been extensively discussed by others. The promise of scientific breakthroughs partly explains this disparity—scientists seeking support for their research programs, and companies building hype for their products, often make bold predictions about the promise of the experimental interventions they are researching, and this can sound convincing when it is put in the language of genomics, proteomics, precision medicine, personalized medicine, and evidence-based medicine. Unwarranted optimism may be based in part on a history of a few successful magic bullets, such as penicillin and insulin—magic bullet thinking gets inappropriately adopted in premature proclamations of game-changing medical interventions, which media outlets promulgate.

Medical nihilism is not the thesis that there are no effective medical interventions. Please do not confuse this. Medical nihilism is, rather, the thesis that there are fewer effective medical interventions than most people assume and that our confidence in medical interventions ought to be low, or at least much lower than is now the case.

As I said, an unconventional and controversial view. We do need measures to assess facts and knowledge, philosophy is not enough. Anyway, I recommend its reading.

Are Pharmaceutical Companies Earning Too Much?

Are Pharmaceutical Companies Earning Too Much?

Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018

The debate about pharmaceutical companies earnings is a never ending story. Now you can find in JAMA an article that reflects the cost of a new drug: $1336 million. This is the summary:

The FDA approved 355 new drugs and biologics over the study period. Research and development expenditures were available for 63 (18%) products, developed by 47 different companies. After accounting for the costs of failed trials, the median capitalized research and development investment to bring a new drug to market was estimated at $985.3 million (95% CI, $683.6 million-$1228.9 million), and the mean investment was estimated at $1335.9 million (95% CI, $1042.5 million-$1637.5 million) in the base case analysis. Median estimates by therapeutic area (for areas with ≥5 drugs) ranged from $765.9 million (95% CI, $323.0 million-$1473.5 million) for nervous system agents to $2771.6 million (95% CI, $2051.8 million-$5366.2 million) for antineoplastic and immunomodulating agents.

Why this new figure is relevant? Because previous estimates said that it was the more than the double!

The mean estimate of $1.3 billion in the present study was lower than the $2.8 billion (in 2018 US dollars) reported by DiMasi et al,

And   my impression is that we have entered in a difficult world to estimate the real cost. Right now many firms are buying research (buying firms that have already a product close to be commercialised) and they are paying a premium for outsourcing research. Therefore, how to estimate the cost in this situations? Uncertain.

David Cutler asks about the earnings of pharma firms and says:

Ledley showed that from 2000 to 2018, the median net income margin in the pharmaceutical industry was 13.8% annually, compared with 7.7% in the S&P 500  sample. This difference was statistically significant, even with controls, although earnings seemed to be declining over time.

Is this positive return differential evidence of too high a return? Not necessarily. The economics of pharmaceuticals are important to consider. Like several other industries (eg, software and motion picture production), the pharmaceutical industry has very high fixed cost and very low marginal cost. It takes substantial investment to discover a drug or develop a complex computer code, but the cost of producing an extra pill or allowing an extra download is minimal. The way that firms recoup these fixed costs is by charging above cost for the product once it is made. If these upfront costs are not accounted for, the return on the marketed good will look very high.

 Paying more than a drug is worth clinically is not a good strategy. Even if a drug is worth a high price socially, pricing patients who need the drug out of the market is a real loss, even if it leads to more innovation in the future. In still another case, price increases for older, generic drugs serve no innovation purpose. But, as a general rule, it is important to be wary of blunt “lower all drug prices” policies.

Cutler doesn't say too much on price according value and about public funding of research. It leaves the initial question open and waiting for adhoc answers. That's it , it's a complicated issue, no general prescriptions, they need to be adjusted to specific conditions without a captured regulator. This last point is the most difficult one to overcome.

Prix Pictet

How to stop ineffective and harmful medical practices

Ending Medical Reversal: Improving Outcomes, Saving Lives

What are medical reversals? We expect that medicine will progress in a generally orderly fashion, with good medical practices being replaced by better ones. We used to use cholestyramine—a horribly tolerated drug that had no effect on patients’ life expectancy—to lower cholesterol after heart attacks. Now we use atorvastatin, a well-tolerated drug backed by robust evidence that it saves lives. This is how medical practice should evolve. Reversal, however, is different. Reversal occurs when a currently accepted therapy is overturned, found to be no better than the therapy it replaced. This often occurs when a practice—a diagnostic tool, a medicine, a procedure, or a surgical technique—is adopted without a robust evidence base.

 Instead of the ideal, which is replacement of good medical practices by better ones, medical reversal occurs when a currently accepted therapy is overturned—found to be no better than the therapy it replaced. Now, you might argue that this is how science is supposed to proceed. In high school, we learned that the scientific method involves proposing a hypothesis and testing to see whether it is right. This is true. But what has happened in medicine is that the hypothesized treatment is often instituted in millions of people, and billions of dollars are spent, before adequate research is done. Not surprisingly, sometimes the research demonstrates that the hypothesis was incorrect and that the treatment, which is already being used, is ineffective or harmful.

So what?

Our medical system is too tolerant of unproven practices. Doctors are too comfortable recommending a practice without real knowledge of whether it is helping or hurting patients. People are too willing to accept practices that seem like they should help. When a medical reversal does occur, most physicians consider it an exception to the rule. 

We need a culture change in medicine. We need to recommit to evidence-based medicine and realize that it is the only rational way to provide care. In this book we have provided a few suggestions for ways we can improve. We do not advocate that these recommendations be immediately implemented but that they be carefully considered, alongside recommendations proposed by other thoughtful analysts, and tested in prospective trials. As we move forward, we must recognize that drastic and dramatic change can often be harmful. We acknowledge that there will be areas of medicine in which, for now, we must tolerate the status quo. As we go through the house of medicine and clean up each room, we have to prioritize.  

Well, let's say that the book focuses on the shadows of medicine, but this is only one part. Generalisations are inacurate. Anyway, good to review it. And medical education is not enough to solve the issue, incentives and culture play a crucial role.

The opportunity costs of excessive medical practice variations

 Atlas de utilización de procedimientos de dudoso valor. Actualización datos 2017

From the new report on practice variations:

La literatura científica abunda en estimaciones de la proporción de asistencia sanitaria cuyo valor para el paciente es cuando menos escaso. Este cuerpo de evidencia no ha hecho sino crecer en la última década, dando origen a varias iniciativas tanto académicas como gubernamentales para identificar y abordar lo que se considera uno de los principales problemas de los sistemas sanitarios modernos. Hay consenso: se trata de un fenómeno altamente prevalente que pone en cuestión el buen uso de los recursos sanitarios.
La actividad sanitaria de dudoso valor incluye tanto la utilización de procedimientos escasamente efectivos o para los que existen alternativas superiores, como el uso de intervenciones efectivas en indicaciones en las que los beneficios para el paciente son prácticamente nulos y en ocasiones incluso generan efectos negativos. Obviamente, para el sistema sanitario y la sociedad que destina los recursos necesarios, el coste oportunidad derivado de este tipo de actividad es sustancial.

So many years talking about it and nothing happens...

Great report, something should be done.
 Angulo-Pueyo E, Seral-Rodríguez M, Ridao-Lopez M, Estupiñán-Romero F, Martínez-Lizaga N, Comendeiro-Maaloe M, Ibañez-Beroiz B, Librero-López J, Millán-Ortuondo E, Peiró-Moreno S, Bernal-Delgado E, por el grupo Atlas VPM. Atlas de variaciones en la práctica médica en utilización de procedimientos de dudoso valor en el Sistema Nacional de Salud, 2017. Marzo 2020; Disponible en: www.atlasvpm.org/atlas/desinversion-2017

PS. Some books I'm waiting for.

Key Indicators for Health

Leading Health Indicators 2030: Advancing Health, Equity, and Well-Being

Hyper-personalized medicine is just starting

If DNA is like software, can we just fix the code?

 10 Breakthrough Technologies 2020

From technology Review:

Here is our annual list of technological advances that we believe will make a real difference in solving important problems. How do we pick? We avoid the one-off tricks, the overhyped new gadgets. Instead we look for those breakthroughs that will truly change how we live and work.

• Unhackable internet

• Hyper-personalized medicine

• Digital money

• Anti-aging drugs

• AI-discovered molecules

• Satellite mega-constellations

• Quantum supremacy

• Tiny AI

• Differential privacy

• Climate change attribution

What hyper-personalized medicine stands for?

Here’s a definition of a hopeless case: a child with a fatal disease so exceedingly rare that not only is there no treatment, there’s not even anyone in a lab coat studying it. “Too rare to care,” goes the saying.
That’s about to change, thanks to new classes of drugs that can be tailored to a person’s genes. If an extremely rare disease is caused by a specific DNA mistake—as several thousand are—there’s now at least a fighting chance for a genetic fix.
One such case is that of Mila Makovec, a little girl suffering from a devastating illness caused by a unique genetic mutation, who got a drug manufactured just for her. Her case made the New England Journal of Medicine in October, after doctors moved from a readout of her genetic error to a treatment in just a year. They called the drug milasen, after her.
The treatment hasn’t cured Mila. But it seems to have stabilized her condition: it has reduced her seizures, and she has begun to stand and walk with assistance.
Mila’s treatment was possible because creating a gene medicine has never been faster or had a better chance of working. The new medicines might take the form of gene replacement, gene editing, or antisense (the type Mila received), a sort of molecular eraser, which erases or fixes erroneous genetic messages. What the treatments have in common is that they can be programmed, in digital fashion and with digital speed, to correct or compensate for inherited diseases, letter for DNA letter.
How many stories like Mila’s are there? So far, just a handful.
But more are on the way. Where researchers would have once seen obstacles and said “I’m sorry,” they now see solutions in DNA and think maybe they can help.
The real challenge for “n-of-1” treatments (a reference to the number of people who get the drug) is that they defy just about every accepted notion of how pharmaceuticals should be developed, tested, and sold. Who will pay for these drugs when they help one person, but still take large teams to design and manufacture?
—Antonio Regalado

Allocating drugs by lottery

Health ministers condemn Novartis lottery for Zolgensma, the world’s most expensive drug

Novartis has held the first draw to choose four babies who will receive its one-shot treatment for the genetic disease spinal muscular atrophy, Zolgensma (onasemnogene abeparvovec), amid criticism of its lottery programme from patient groups and EU health ministers.
Priced in the United States at $2.1m (£1.6m; €1.9m), the most expensive drug course of treatment ever, Zolgensma is not yet approved elsewhere. In December the company announced a plan to give away 50 treatments in other countries over the next six months, the recipients to be chosen randomly from among applicants every two weeks.
Recipients must be under 2, the upper age limit for which the drug is approved in the US. Most of the children in the Zolgensma draw were registered by their doctors. About one child in every 8000 live births is born with spinal muscular atrophy. The most severe type, called type 1 or Werdnig-Hoffmann disease, usually causes death during early childhood if untreated.

Does this makes any sense? In my opinion is a perfect strategy (for Novartis) to create artificial  scarcity. It is a well known approach to increase willingness to access/ willingness to pay. It was described by Adam Brandenburger in a book long time ago: Coopetition.
I hope it will not succeed (at least in Europe).

David Hockney

Predictive modeling in health care (2)

Data-Driven Approaches for Health Care Machine Learning for Identifying High Utilizers

Predicting health outcomes using data modeling approaches is an emerging field that can reveal important insights into disproportionate spending patterns. This book presents data driven methods, especially machine learning, for understanding and approaching the high utilizers problem, using the example of a large public insurance program.

Five years ago I explained in this blog our experience on predictive modeling. This a key reference book.

Confidential drug pricing without confidential prices

Performance-based managed entry agreements for new medicines in OECD countries and EU member states: How they work and possible improvements going forward

In this blog I've explained my position against confidential prices for drugs. However, there is an option to complicate it: confidential entry agreements. This is the current trend for high cost drugs with uncertain outcome. The report of the OECD explains the current situation in different countries and helps to shed light in this important issue. Just take this short statement and you'll be convinced of the complete mess:

It is difficult to assess to what extent performance-based MEAs have so far been successful. Few countries have formally evaluated their experience. Confidentiality of agreements continues to be a barrier to independent evaluation and little evidence is public. However, information available from expert interviews and from prior studies indicates that CED agreements have so far had a poor track record of reducing uncertainty around the performance of medicines. As a result, some countries have recently reformed CED schemes and some are discontinuing CED agreements altogether in favour of alternatives. The latter include restricted or conditional coverage without a MEA, whereby coverage is initially restricted to certain indications or patient groups and only broadened if and when additional evidence becomes available. Payment-by-result agreements continue to be used quite widely, but they do not always generate evidence
on product performance because data used for triggering payments are not always  aggregated and analysed.

Sophia Al-Maria at Tate

Trade-offs in algorithmic clinical decision making

On the ethics of algorithmic decision-making in healthcare

Great article.

Clinicians, or their respective healthcare institutions, are facing a dilemma: while there is plenty of evidence of machine learning algorithms outsmarting their human counterparts, their deployment comes at the costs of high degrees of uncertainty. On epistemic grounds, relevant uncertainty promotes risk-averse decision-making among clinicians, which then might lead to impoverished medical diagnosis. From an ethical perspective, deferring to machine learning algorithms blurs the attribution of accountability and imposes health risks to patients. Furthermore, the deployment of machine learning might also foster a shift of norms within healthcare. It needs to be pointed out, however, that none of the issues we discussed presents a knockout argument against deploying machine learning in medicine.

Repairing DNA: a review

The promise and challenge of therapeutic genome editing

Jenifer Doudna publishes a must read review article on genome editing in Nature this week. 

Current clinical trials using the CRISPR platform aim to improve chimeric antigen receptor (CAR) T cell effectiveness, treat sickle cell disease and other inherited blood disorders, and stop or reverse eye disease. In addition, clinical trials to use genome editing for degenerative diseases including for patients with muscular dystrophy are on the horizon.

 Notably, all of the genome-editing therapeutics under development aim to treat patients through somatic cell modification. These treatments are designed to affect only the individual who receives the treatment, reflecting the traditional approach to disease mitigation. However, genome editing offers the potential to correct disease causing mutations in the germline, which would introduce genetic changes that would be passed on to future generations.

 At the time of writing, international commissions convened by the World Health Organization (WHO) and by the US National Academy of Sciences and National Academy of Medicine, together with the Royal Society, are drafting detailed requirements for any potential future clinical use.

Meanwhile, CRISPR is closer than you think.

Fig. 1: Ex vivo and in vivo genome editing to treat human disease.

Fig. 2: The genome editing toolbox.

Fig. 3: Emerging tools.

Fig. 4: Editing the human germline.