Deep Learning in Pathology

Here is an intersting article, showing the role of AI in pathological diagnoses. Medical speciliaties most dependent on pattern recognition, such a pathology, dermatology, or radiology, are more likely to get AI assistance sooner. With time, it is quite possible that AI can replace such physicians. For now, it appears that AI will help them work faster. Remember, increasing efficiency means need for fewer physicians in such specilaties and possibly decliing salary.

Incentives and Work

An interesting article which is also very germane to academic physicians. In particular the sentence “what drives most academics to the university on a given day (including evenings and weekends) is not the money (otherwise we would work in the private sector) or the stability of the income stream (because the probability of losing a job is close to zero for a tenured academic). In fact, Stern (2004) shows that “scientists pay to be scientists.”  is right on the spot. One can say about physicians in academia that they “pay to be in academics”. In almost every case, they can earn quite a bit more in private practice. It is the meaning in their work that motivates them.

Aspirin and Body Weight

Low dose aspirin has been shown to reduce cardiovascular events but the observed effect may vary by weight. In fact, in one of our studies, we have shown that not only obese individuals had greater baseline platelet reactivity, they also had greater residual platelet reactivity after low-dose aspirin therapy. Comparing obese and nonobese individuals after aspirin therapy, results for aggregometry to collagen were 6.7 vs 6.1 ohms, P=.008; aggregometry to adenosine diphosphate were 13.1 vs 11.8 ohms,P<.0001; aggregometry to arachidonic acid (AA) were 4.9% vs 8.3% nonzero aggregation, P=.002; urinary excretion of 11-dehydro-thromboxane B2 (Tx-M) were 4.9% vs 8.3% nonzero aggregation, P=.002; and aspirin resistance were 26.% vs 20.5%, P=.002; respectively.

Now an individual-patient meta-analysis of primary prevention randomized controlled trials with low-dose aspirin have shown that clinical outcomes are also different in patients with weight>70Kg than in patients with weight<70Kg. On the other hand, when a higher dose of aspirin was examined, individuals with weight>70Kg obtained clinical benefits. Clinical benefits were not limited to cardiovascular outcomes but also included colorectal outcomes.

An obvious implication of such studies is that individuals with weight>70Kg should take perhaps more than one baby aspirin to receive benefit from aspirin.

Artificial Intelligence & Medicine

Some recent articles ……

Goldberg JE, Rosenkrantz AB. Artificial Intelligence and Radiology: A Social Media Perspective. Current Problems in Diagnostic Radiology. 2018 Jul 23.
An interesting study examining the types of conversations on Twitter about the role of artificial intelligence in radiology. It appears that most tweets (or linked websites) were upbeat and wanted radiologists to continue supervision of AI-run diagnostics.

Meskó B, Hetényi G, Győrffy Z. Will artificial intelligence solve the human resource crisis in healthcare?. BMC health services research. 2018 Dec;18(1):545.
This article expresses the hope that artificial intelligence may be able to help in mitigating human resource crisis in health sector.

dos Santos DP, Giese D, Brodehl S, Chon SH, Staab W, Kleinert R, Maintz D, Baeßler B. Medical students' attitude towards artificial intelligence: a multicentre survey. European radiology. 2018 Jul 6:1-7.
This article examines the attitudes of undergraduate medical students towards artificial intelligence in radiology and medicine. Students think that artificial intelligence will revolutionize the practice of medicine, in particular radiological diagnosis.

Struggling Healthcare Organizations

A systematic review identified five characteristics of healthcare organizations that are struggling to improve quality.

1.  Poor organizational culture: Such as limited ownership, not collaborative, hierarchical, with disconnected leadership

2. Inadequate infrastructure: Limited quality improvement, staffing, information technology or resources

3. Lack of a cohesive mission: Mission conflicts with other missions, is externally motivated, poorly defined or promotes mediocrity

4. System shocks: Events such as leadership turnover, new electronic health record system or organizational scandals that detract from daily operations

5. Dysfunctional external relations with other hospitals, stakeholders, or governing bodies.

Physician Competition Effects

An interesting study examined the impact of competition among cardiologists on service provision and patients' health outcomes in the United States. Authors found that cardiologists in more concentrated markets perform more diagnostic procedures. On the other hand, higher concentration result in fewer readmissions but has no effect on mortality.

Medical Bill Collections Decrease with Patient’s Age

An interesting study that finds that the average size of medical debt decreased nearly 40 percent from when patient was twenty-seven old to when sixty-four years old. Authors thought that this was with an increase in health insurance coverage and incomes.

Well-being–some readings

Well-being has been a focus of philosophers for centuries. While philosophers tend to question how we should live, the very answer to this question begs the question how living that way will make us better, that is, how living in a certain way will make us live well.

A little self-reflection will help you to realize that there are many things that make you live well, make you happy, excited, or content, or conversely make you feel sad. Think of the things that make you feel happy. Often these things include relationships, friends, money, accomplishments. Now think of things that make you feel sad; these may include anxiety, worry, illness, poverty. Lists of both things, things that make us happy and things that make us sad, can be long and likely will vary from person to person (at least to some extent). The question one may ask is what is it that one thing (or a small group of things) that is fundamentally deterministic of feeling well.

Hedonism is a theory of well-being which focuses on individual’s pleasure or pain. Thus, pleasure is associated with high well-being and pain is associated with poor well-being. On the other hand, perfectionism focuses on our ability to develop certain virtues or characteristics. Perfectionism is similar to eudaimonia; well-being is associated with developing virtues that are human nature. Desire theory proposes that well-being is present when one gets what one desires; in other words, fulfillment of desires is associated with well-being. Objective list theories are a set of theories that have in common a list of things that make one happy; list from one theory may not overlap with another theory. This group of theory highlight the fact that it is not easy to define what constitute well-being.

Machine Learning Predicts Clinical Deterioration

Edelson and her colleagues trained a gradient boosted machine model on a dataset of almost 300K patients and were able to predict clinical deterioration better than the modified early warning (MEWS) system. Here is the link for the abstract that was presented at ATS 2018.

The simplicity of the tool which uses only age, heart rate, and respiratory is really impressive. Interestingly, respiratory rate is often the least accurately measured vital sign in the hospitals despite its simplicity. A more accurate measurement of respiratory rate can potentially help better predictive models to predict clinical worsening in a patient’s condition. Better prediction can not only help to patients by focusing on the cause of clinical worsening but will also help to more optimally utilize resources within the hospital.

Some Interesting Recent Articles from bioRxiv

1. The Subtype Specificity of Genetic Loci Associated with Stroke in 16,664 cases and 32,792 controls: Using Bayesian multinomial regression in 16,664 stroke cases and 32,792 controls of European ancestry, investigators wanted to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations. Of the 16 loci, seven influenced both ischemic and hemorrhagic stroke, an EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction.

2. Sensitivity to Affective Touch Depends on Adult Attachment Style: Higher scores on an attachment anxiety dimension (but not an attachment avoidance) were associated with reduced pleasantness discrimination between affective vs. non-affective, neutral touch.

3. The GRE Over the Entire Range of Scores Lacks Predictive Ability for PhD Outcomes in the Biomedical Sciences: GRE scores are often assumed to be predictive of student success in graduate school; however, authors found no association in admission data.

MIMIC Database

I ran across this publicly available dataset which looks great for someone interested in data-analysis. The dataset appears to be extensive. I have not worked with its analysis yet but this will be something that will be on my ‘things-to-do” list. According to its website “MIMIC is an openly available dataset developed by the MIT Lab for Computational Physiology, comprising deidentified health data associated with ~40,000 critical care patients. It includes demographics, vital signs, laboratory tests, medications, and more.”

Proposed Changes to Medicare Physician Fee Schedule 2018

Last week, the Centers for Medicare & Medicaid Services (CMS) proposed a rule to update payment policies, payment rates, and quality provisions for services furnished under the Medicare Physician Fee Schedule (PFS) on or after January 1, 2019. Some of the proposed changes include:

1. Streamlining E&M payment with reduction in clinical documentation burden

2 .Recognition of services based on the use of communication technology

3. Creation of a bundled episode of care for substance abuse disorders

4. Flexibility on the use of radiology assistants

5. Removing functional status reporting requirement for outpatient treatment

6. A slight increase of $0.06 per RVU

7. Updating the direct practice expenses based on recent survey

8. Medicare telehealth services

9. Request for information on price transparency

10. Changes to the Quality Payment Program

Here is the link for those interested in learning more about these proposed changes

Physician White Coats and Patient Preference

An interesting study published in the BMJ Open and an interesting overview here by Brad Flansbaum.

Bottom line, formal physician attire with a white coat was rated significantly higher by patients than any other attire. Just an re-emphasis on the fact that ‘packing’ matters. One may want to to look at this that those physicians who take their profession seriously also try to wear a better representative attire than others; I am sure there a large number of physicians who may strongly disagree with this assessment.

Vitamin D Levels in African Americans

Vitamin D is associated with bone and calcium metabolism. However, more recently, studies have increasingly reported the effect of vitamin D on other organs and systems. For example, vitamin D is associated with all-cause mortality and cardiovascular mortality. Vitamin D is also associated with peripheral arterial diseases. Further, vitamin D has been associated with serum C-reactive protein levels (a biomarker of systemic inflammation). Vitamin D has also been associated with liver function.

African Americans tend to have significantly lower levels of serum vitamin D and hence may be at a higher risk of low vitamin D related morbidity. The reason perhaps lies in genetics, at least that is what this study suggests. Investigators assessed the association between percentage of European ancestry and serum vitamin D level among 2,183 African-American women. An algorithm implemented through a software was used to estimate the percentage of European ancestry versus African ancestry in each individual. After adjustment for various potential confounders (genotype batch, age, body mass index, supplemental vitamin D use, ultraviolet B radiation flux in the participant’s state of residence, and season of blood draw), investigators reported that each 10% increase in European ancestry was associated with a 0.67-ng/mL increase in serum vitamin D concentration (95% confidence interval: 0.17, 1.17).

Question remains if the low serum levels of vitamin D are clinically meaningful in African Americans. Do low serum vitamin D levels are reflective of low tissue levels (or effective tissue levels)? These type of questions will need a different and more involved study designs for answers.

Diabetes and Risk of Cancer

Patients with diabetes mellitus are at increased risk of cardiovascular complications such as heart attack, stroke, peripheral arterial disease etc. Commonly, the cause of death in diabetes is due to cardiovascular events.

Does diabetes increases risk of cancer in addition of increased risk of cardiovascular diseases? This important question was explored in this interesting study of over half-million Chinese. Investigators enrolled patients with and without diabetes and without any prior diagnosis in the study between 2004-2008 and then followed them until the end of 2013 for development of any cancer. During the follow-up period, they found more than 17,000 cases of cancer. Diabetes was associated with an increased risk of all-cause cancer and site-specific cancer.

Diabetes increased the risk of overall cancer by 13%, of liver cancer by 51%, of the pancreatic cancer by 76% and of the breast cancer by 21%. Investigators further reported that higher random blood glucose levels were associated with increased risk of cancer. Perhaps, it is the elevated blood glucose levels in diabetics that is responsible for cancer.

Medical Procedures and Heart Valve Infection

There are not free lunches! It is not uncommon to think that getting a procedure is better than not getting one, however, all procedures are associated with risks. For each procedure, the risk and benefits need to be carefully assessed before making a decision to undergo a procedure or not. Often having a procedure has greater benefits than risks, or so we assume.

While the benefits of a procedure are often clear, for example detection of coronary diseases when deciding about cardiac catheterization, the risks are not as well-studied. The list of risks associated with a procedure almost always includes risk of death and injury to some organ(s) but the actual incidence of these adverse events is usually poorly known, especially for for adverse events that are not immediately followed by the procedure (that is, there is lag-time between a procedure and associated adverse events). The more time lapses between the procedure and an adverse event, the difficult it is to ascribe adverse event to the procedure; generally so many other things, including additional procedures, happen in-between for diagnostic or therapeutic reasons.

One aspect of this issue is nicely addressed in an article published in the Journal of the American College of Cardiology where authors identified all adult patients treated for endocarditis in hospitals in Sweden and compared the occurrence of invasive medical procedures 12 weeks before endocarditis with a corresponding 12-week time period exactly 1 year earlier.

Of the 7,013 cases of infective endocarditis during the study period, several were strongly associated with cardiovascular procedures, especially coronary artery bypass grafting; procedures of the skin and management of wounds; transfusion; dialysis; bone marrow puncture; and some endoscopies, particularly bronchoscopy. A particularly interesting finding, that makes sense, is that the risk of infective endocarditis was higher if patient had a procedure while hospitalized than when patient had that procedure in outpatient setting. One way to look at this is to think that procedures should be done in outpatient setting but the converse is also possible (and more likely) that patients admitted to the hospital are sicker and hence are at higher risk of adverse effects.

Opioid use and voting Republican

A very provocative study by Goodwin et al have found that the chronic use of prescription opioid use was correlated with support for Republication candidate in 2016 Presidential elections. In case someone is concerned if the observed effect is due to the confounding by age (elderly people voting Republican but also having high need for opiates due to chronic diseases), authors did adjust for age and a broad category of other factors. I will invite everyone to read this study oneself.

Odds Ratio Limitations

Odds ratio is perhaps the most commonly reported effect size for binary outcome variables. The widespread use is likely due to the fact that logistics regression models provide odds ratio. Logistic regression models are relatively easy to implement and hence odds ratio is commonly reported. An article in JAMA recently highlighted some of the limitations of using odds ratio. The first two are well-known; the third one is not as well-known and its consequences are not fully realized. 

1) The interpretation is in odds and not in probabilities

2) Odds ratio approximates relative risk in limited situations only

3) Odds ratio depends on the the amount of unexplained variance; odds ratio may increase if the amount of unexplained variation decreases due to inclusion of strong explanatory variables in the model. Odds ratios obtained from same data set but different model may not be comparable due to the above limitation.

Productivity Paradox and EHR

Bob Wachter and Michael Howell are optimistic about the future improvements in health information technology and its impact on physicians. I share their enthusiasm and I am optimistic about an increase in productivity in healthcare sector. And why not? Its about time.

Productivity in every other sector has resulted in decreasing utilization of human resources and increasing production of goods. However, such is not the case in healthcare. A physicians still sees about the same number of patients in a day as he/she used to see 50 or 100 years ago. It is quite possible that the number patients seen might have dropped due to documentation and other requirements. The result is evident; healthcare sector now accounts for almost one-fifth of the GDP in the US. Much of this has to so with the lack of growth in productivity in healthcare sector as compared to other sectors.

What is promising is that artificial intelligence will likely to increase productivity in the healthcare. I don’t think that this will come through improvements in health information technology (HIT). I believe it will come with better utilization of HIT as data repository for learning algorithms. Technology will also help in data capture, and it does so in many ways even now, but most importantly in data inference. However, it will not be good for an average physician.

Remember, productivity can increase only if more patients can be seen by fewer physicians (or healthcare workers). That is not possible with one physician simultaneously seeing several patients. It is possible only when machines see most patients and physician sees patients only in those situations where algorithms have not gotten enough data to develop a routine.

And what those situations will occur in relatively rare conditions. These will not our usual common diseases, what we might call ‘bread-and-butter’ medicine. Rather these will be either rare diseases or rare manifestations of common diseases. A physician overseeing such a highly productive healthcare delivery system will have to be a master clinician and a superb diagnostician.

In other words, an increase in productivity in healthcare sector will spell the doom for majority of physicians ….. happy to hear what you think……….

Hospital Readmissions and Malnutrition

While it is easy to imagine how malnutrition can be related to excess readmissions, there are not very many studies examining this association. Of note, the CMS adjustment algorithm for expected readmissions takes into account malnutrition.

This retrospective study from Australia, examined this association among 26 253 admissions, representing 19 924 patients with a 6-month readmission rate of 44.8%. They found that malnourished patients had 40% higher risk of readmission within first week after discharge and 23% higher risk of readmission between the second week and 23rd week after discharge. Authors concluded that malnutrition was a strong predictor of unplanned readmissions and suggested examination of targeted nutritional interventions to lower readmission rate. 

Artificial Intelligence versus Human Doctors

While it is relatively easy to imagine artificial intelligence taking over pattern recognition type of physician work (such as reading images like radiologists or identify skin conditions by looking at the skin like dermatologists), the job of a general internist is much more demanding and requires assimilation of data inputs from a large number of sources, hence making it difficult for an artificial intelligence system to accurately predict a disease (or prepare a list of differential diagnoses).

On the other hand, the process is not, and should not be, very difficult for a well-crafted system. Razzaki et al tested such an artificial intelligence algorithm and compared it with physicians in its ability to predict diagnosis. For their study, they adopted a semi-naturalistic, role-play paradigm that simulated a realistic consultation between a patient and either their artificial intelligence system or a human doctor. Their study was designed to assess both the clinical (diagnostic and triage) accuracy and the ability to gather all of the relevant history from the patient. What they found was that their artificial intelligence algorithm was able to provide diagnostic and triage advice with a level of accuracy and safety approaching that of human doctors. If there study results are replicated then such systems may not only reduce costs and improve access to healthcare worldwide but may also provide better standardization of care delivered to patients.

Obesity and Increased Risk of Death

It is now well-known that obesity (BMI>29.9) or weight below the normal range (BMI<18.5) are associated with high risk of mortality. On the other hand, just being a little overweight (between 25 and 29.9) may reduce overall risk of death. These results were mainly based on a study published in 2005. However, there were some questions about possible bias due to incomplete adjustments for some risk factors such as smoking.

An update of these results with analysis for potential bias was recently published and available on NHANES website. Basically, the results remained the same and obesity and underweight both groups remained associated with high risk of death.

Of particular interest is the underweight group; while lay media has been focused on obesity, the other extreme, that is being underweight, is also associated with increased risk of death. In fact, the risk of death may be twice as high as normal weight in underweight individuals between the ages of 25 and 59 years.

Nutrition Data in NHANES

Ahluwalia et al published a review article (now updated) that gives a very interesting and comprehensive overview of dietary data collected in NHANES. The data is available publicly and dataset is really large allowing for examination of a large number of hypotheses.

Geographic Rounding and Patient Satisfaction

Geographic rounding is often touted as a way by which healthcare team can communicate better among themselves and thus patient will get similar messages from all team members. Further, team members will appear to patient have strong team-work . Lastly, this will also allow healthcare team to spend more time with patients. Hence, patient satisfaction will increase. While it sounds reasonable in theory, there is little evidence supporting this logical sequence. Siddiqui et al examined this question in their recent study published in the Journal of Patient Experience.

Interestingly, they found that the patients cared for by geographically localized teams did not have better patient experience. They suggest that other factors such as physician communication skills may overshadow the impact of having localized teams. Obviously, further research is needed to better understand organizational, team, and individual factors impacting patient experience.

Phytoestrogens and Liver

Genistein is a phytoestrogen with similarities to female sex hormones and, has been shown to prevent nonalcoholic fatty liver injury in animal studies but human studies are lacking.

In this study, authors, analyzed data from the National Health and Nutrition Examination Survey from 1999 to 2010 and examined the relationship between normalized urinary genistein (nUG) and serum ALT using linear regression models. Investigators further examined the differential effect of sex using an interaction term.

In almost 10K patients, authors found a statistically significant association between genistein and liver function in males, but not in females. At least for me, the sex-specific role of genistein in mitigating liver disease is very interesting.

Sepsis and qSOFA, SIRS, NEWS

Sepsis is a rather common admitting diagnosis to hospital with high mortality rate. Identifying patients who are at a higher risk of adverse outcomes may help to optimize resource allocation. To this end, initially SIRS definition was recommended. More recently, qSOFA is being promoted as a predictor of adverse events during hospitalization due to sepsis. However, there is a lesser known NEWS score that is also being used at few hospitals.
This study compared the three scores in a retrospective sample and found that NEWS may be similar or superior to qSOFA. Note that qSOFA (3 variables) is the quickest and simplest of the three while NEWS is the most complex (20 variables).

A Fantastic Weekly Update on Artificial Intelligence

I have been enjoying this weekly update by Azeem Azhar. And I invite you to try it too. Here is the link

http://www.exponentialview.co

SES Adjustment for Readmission Penalty

CMS started implementing the Hospital Readmissions Reduction Program (HRRP) on October 1, 2013, penalizing hospitals with higher readmission rates. While readmission rates were adjusted for several factors, socioeconomic status (SES) was missing leading to protests and lobbying by hospitals caring for poor people. Hence, in 2016 the US Congress directed the CMS to to adjust for low SES. In response, CMS has made following adjustments to HRRP.

1. Make five peer groups of hospitals based on SES. SES will be determined by the proportion of “dual eligible” Medicare beneficiaries (those who are also eligible for full Medicaid benefits).
2. Calculate the median excess readmission ratios (ERRs) within each peer group to adjust for penalties
3. Scale penalties using the budget neutrality factor.

Fuller and colleagues analyzed the effect of SES adjustments (as outlined above) and examined the effect on the number and distribution of penalized hospitals. An interesting read!

Protection of Gut Microbiome from Antibiotics

While antibiotics are essential for treatment of bacterial infection, an increasingly recognized adverse effect of antibiotic use is alteration in gut microbiome. The altered gut microbiome can result in several acute and long-term unhealthy effects. This small clinical trial tests the use of an adsorbent to to mitigate the effects of antibiotics on gut microbiome. Investigators found, using the shotgun quantitative metagenomics, that the richness and composition of the intestinal microbiota were largely preserved in subjects using antibiotics when co-treated with DAV132 (the adsorbent used in this study). This is an important study, and if the adsorbent is effective without compromising the antibiotic availability in blood, may be extremely useful in clinical medicine. 

Geographic Latitude, Blood Pressure, and Serum Cholesterol

This is a provocative study pointing out the association of geographic latitude with serum cholesterol levels. Obviously such studies, at country level, are fraught with biases including ecological fallacy. However, the underlying etiology of the observed differences need to be explored further.

Designing a RCT and Network Meta-analysis

A review of literature with possible meta-analysis of available data is often recommended before a randomized clinical trial (RCT) can be proposed. This article goes a step further and suggests using network meta-analysis for planning and designing a RCT. Authors emphasize that a trial design based on updating the evidence from a network meta-analysis of relevant previous trials may require a considerably smaller sample size to reach the same conclusion compared with a trial designed and analyzed in isolation.

Weak vs. Strong Social Ties

The relative contribution of the number of strong social ties versus the number of weak social ties to the health status was explored in this study. Authors examined social network characteristics as predictors of mortality in the Finnish Public Sector Study (n = 7,617) and the Health and Social Support Study (n = 20,816). At baseline, social network characteristics were surveyed. During a mean follow-up period of 16 years, participants with a small social network (≤10 members) were more likely to die than those with a large social network (≥21 members) (adjusted hazard ratio (HR) = 1.23, 95% confidence interval (CI): 1.04, 1.46). Mortality risk was increased among participants with both a small number of strong ties (≤2 members) and a small number of weak ties (≤5 members) (HR = 1.55, 95% CI: 1.26, 1.79) and among participants with both a large number of strong ties and a small number of weak ties (HR = 1.28, 95% CI: 1.08, 1.52), but not among those with a small number of strong ties and a large number of weak ties (HR = 1.04, 95% CI: 0.87, 1.25). Authors conclude that the number of weak ties may be an important component of social networks for mortality risk.

Diagnostics After Multilevel Regression in Stata

Here are few diagnostics that can be run in Stata after running a multilevel model

1. Assess normality of residuals

predict resid_std, rstandard
qnorm resid_std

2. Examine relationship between predicted and residual values

predict resid, res
predict fit, fit

3. Examine variance-covariance matrix

estat recovariance
estat recovariance, correlation

4. Determine Cook’s D and DFBETAs using MLT module

net install mlt.pkg    /* Installs MLT package*/
mltcooksd              /* reports Cook’s D of the whole model */
mltcooksd, fixed       /* reports Cook’s D of the Fixed part */
mltcooksd, random      /* reports Cook’s D of the Random part */
mltcooksd, approx      /* Uses approximation and returns results faster */

A very easy and simple video explaining Bayes Theorem

Must watch TED talk

Talks about how artificial intelligence algorithms are able to affect our opinions. We all are vulnerable, yes we ALL are.

Case against propensity scores

Here is an interesting video (couple of years old but still relevant)

CLABSI Trends and Parenteral Nutrition

Healthcare-associated infections (HAIs) harmful for patients and costly for the health system. Central line associated bloodstream infections (CLABSI) are the most costly of HAIs (between 45K to 55K per CLABSI), increase length of stay by several days, and increase mortality by 15% to 40%. Although the rate of CLABSI has been decreasing since the institution of several preventive practices, the rates remain pretty high.

Patients who receive parenteral nutrition have more than 4-times higher risk of CLABSI than those who who do not receive parenteral nutrition. However the data on the risk of CLABSI risk since the institution of penalties for CLABSI by CMS (Centers for Medicare & Medicaid Services) was not available, that was until the publication of study by Fonseca et al. They used data from all adult patient discharges between January 1, 2009, and December 31, 2014, from 2 affiliated hospitals in a large health system in New York City. They conducted univariate and multivariate analyses to examine the relationship and temporal trends between parenteral nutrition and CLABSIs.

Of the 38,674 patients with central lines, 3517 developed CLABSIs. Of these 3517 patients, 767 patients were prescribed parenteral nutrition. Patients who were prescribed parenteral nutrition were 2.65 times more likely to have CLABSI than patients without parenteral nutrition. What this study shows is that there has been a decrease in the risk of CLABSI among patients who receive parenteral nutrition, although the risk remains much higher. Obviously, this study advocates for additional research to identifies strategies to decrease the risk of CLABSI in patients who receive parenteral nutrition.

Burnout

Burnout among healthcare workers, particularly physicians, has gained increasing attention recently. The societal expectation is that physicians will be selfless and put their patient’s needs first. Often physicians are expected to work long hours and do whatever it takes to help their patient and to go the extra mile; in other words give one's all. Burnout is further exacerbated by the changes in national health system and healthcare organizations; such changes are resulting in work environments that are high in demands and low in resources.

However, what is burnout is open to interpretation. Experts still debate about the dimensions of burnout. The most common burnout measurement tool, Maslach Burnout Inventory (MBI) assumes three dimensions of burnout; emotional exhaustion (EE), depersonalization (DP), and personal accomplishment (PA). MBI has been criticized for its various aspects. For example, it measures three dimensions of burnout (EE, DP, PA) but recommends against merging those three dimensions to reach to the measurement of burnout itself. Thus, MBI is measuring three concepts but unable to define a single concept of burnout. Another criticism is that burnout is an amalgam of an individual state (EE), an undesirable coping strategy (DP), and result of the EE state (lack of PA). However, the biggest criticism of MBI is that it is not available in public domain.

The dimensions of burnout are open for discussion. While MBI, as noted above, considers that burnout has three dimensions, others consider burnout to have two or even one dimension; it is possible that burnout may have more than 3 dimensions. For example, Oldenburg Burnout Inventory considers only two dimensions of burnout out while Copenhagen Burnout Inventory (CBI) considers only one dimension of burnout.

Obviously, the disagreements about the definition and dimensions of burnout limit the study of effective interventions and have lead some to suggest that burnout perhaps does not exist as a separate entity on its own.

CHADS-VASc Score predicts stroke and death in congestive heart failure patients

The CHA₂DS₂-VASc score (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is used clinically for stroke risk stratification in atrial fibrillation (AF). However, whether it can predict these outcomes in patients with heart failure remained unknown.

Melgaard et al, examined the nationwide prospective cohort study using Danish registries, including 42,987 patients (21.9% with concomitant AF) not receiving anticoagulation who were diagnosed as having incident HF during 2000-2012.

In patients without AF, the risks of ischemic stroke, thromboembolism, and death were 3.1% (n = 977), 9.9% (n = 3187), and 21.8% (n = 6956), respectively.  The risks were greater with increasing CHA₂DS₂-VASc scores. Interestingly, the absolute risk of thromboembolic complications was higher among patients without AF compared with patients with concomitant AF at high CHA₂DS₂-VASc scores. However, predictive accuracy was modest, and the clinical utility of the CHA₂DS₂-VASc score in patients with HF remains to be determined.

Treatment of Abdominal Aortic Aneurysm

What is a better treatment option for patients with abdominal aortic aneurysms (AA)? Currently, there are two main options; endovascular repair (below left) or open surgical repair (below right).

Chang and his colleagues analyzed the longitudinally linked California Office of Statewide Health Planning and Development inpatient database from 2001 to 2009 with a median follow-up of 3.3 years. They studied 23,670 patients, with 52% receiving endovascular repair. Endovascular repair was associated with improved 30-day outcomes (all-cause mortality, readmission, surgical site infection, pneumonia, and sepsis), as well as significantly improved survival until 3 years postoperatively. After 3 years, mortality was higher for patients who underwent an endovascular repair. No significant difference in long-term mortality was observed for the entire cohort on adjusted analysis (hazard ratio, 0.99; 95% CI, 0.94-1.04; P = .64). Endovascular repair was found to be associated with a significantly higher rate of re-interventions and AAA late ruptures.

Some Stuff from ESC

 

Warfarin Discontinuation Increases Stroke Risk

Non-steroidal Mineralcorticoid Receptor Antagonist Could Cut Mortality

One study says:
- Stimulation of either the right or left vagus nerve appeared to improve cardiac function in patients with heart failure
And other one says:
- Stimulating the vagus nerve didn't improve cardiac function in heart failure patients
Go figure!

Antidote for Dabigatran

Until recently, warfarin (also known as Coumadin), a vitamin K antagonist (VKA), had been the only available oral anticoagulant. The use of warfarin has been always complicated by many issues including its narrow therapeutic index and multiple drug and diet interactions affected its safety, compliance, and efficacy. Patients needed regular and close monitoring of the its anticoagulant effect (how thin is blood?). Despite regular monitoring, patients suffered bleeding complications when blood was too thin (supra-therapeutic range) or blood was thin within the desired range but other patient factors (such as trauma/injury) resulted in bleeding.

A very common use of warfarin is for anticoagulation in patients who suffer from atrial fibrillation. With increasing age, the risk of atrial fibrillation increases and atrial fibrillation is common older individuals. Patients with atrial fibrillation can develop a clot in the left atrium of the heart and this clot can dislodge and go to other parts of the body. If this dislodged clot goes to arteries that supply blood to the brain, it usually results in large stroke. The risk of stroke with atrial fibrillation varies from person to person but can be calculated using a CHADS2 score and may vary from 1.8% per year to 18% per year without anticoagulation.

The above noted problems with warfarin prompted the development of new oral anticoagulants that target key coagulation proteins. Within past few years, FDA has approved several new oral anticoagulants that don’t require regular monitoring with blood tests and have very few drug interactions. However, one limitation with these new anticoagulants is lack of an antidote that can quickly reverse the effect of these drugs in cases of emergency, such as when a patient is bleeding. On the other hand, vitamin K can be used to reverse the effect of warfarin. Several pharmaceutical companies and other research groups are trying to develop agents that can effectively reverse the effects of these new anticoagulants.

Pollack and colleagues have published in this issue of the New England Journal of Medicine a trial of such an antidote of dabigatran, an oral thrombin inhibitor that is approved for the prevention of stroke in patients with non-valvular atrial fibrillation and for the prevention and treatment of venous thromboembolism. Investigators used idarucizumab, a monoclonal antibody fragment that binds dabigatran with an affinity that is 350 times as high as that of dabigatran’s affinity with thrombin (a coagulant protein through which dabigatran acts). In blood, idarucizumab binds free and thrombin-bound dabigatran and neutralizes its activity. In this prospective cohort study, investigators examined the safety of 5 g of intravenous idarucizumab and its inhibitory effect on dabigatran in patients who had serious bleeding (group A) or who required an urgent procedure (group B). Investigators determined the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab (primary endpoint).

Of the 90 patients who received idarucizumab (51 patients in group A and 39 in group B), idarucizumab normalized the blood coagulation in 88 to 98% of the patients often within minutes. Concentrations of unbound dabigatran was below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, bleeding was controlled at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.

As noted above idarucizumab is specific for dabigatran and is unlikely to be effective with other new oral antocagulants. However, various reversal agents and/or strategies, nonspecific to dabigatran, are available to physicians, including prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa.

Southern Dietary Pattern and Heart Disease

We are what we eat – and the diseases we get are the often (at least partly) a result of dietary choices we make.

A study published in the American Heart Association’s journal, Circulation, finds that people who have Southern dietary pattern – characterized by added fats, fried food, eggs, organ and processed meats, and sugar-sweetened beverages – are at a higher risk of heart attacks and sudden cardiac death. Investigators analyzed data from 17,418 participants in Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national, population-based, longitudinal study of white and black adults aged ≥45 years, enrolled from 2003-2007. They found 56% higher risk of heart attacks and sudden cardiac death among individuals who eat ‘Southern’ food than those who rarely eat such food.

So next time when you are thinking about what to eat, chose something healthy!

Updated Guidelines - Diabetics and Cardiovascular Disease

American Heart Association and American Diabetes Association has recently published an update to the guidelines for the prevention of cardiovascular disease in adults with type 2 diabetes mellitus. There are certain interesting aspects to it.

1. Use of Hemoglobin A_1C for the diagnosis of diabetes mellitus
 Pre-diabetes = A_1C between 5.7% and 6.4%
Diabetes Mellitus = A_1C >/= 6.5%

2. Lifestyle Management of Diabetes
Physical Activity
Nutrition
Weight Reduction (through physical activity, nutrition, weight-loss drugs, and/or bariatric surgery)

3. Cardiovascular risk reduction
Control of blood glucose (A_1C <7%)
Control of blood pressure (< 140/90)
Control of Cholesterol (statins)
Aspirin for moderate 10-year CVD risk (5-10%)

4. Screening for cardiovascular diseases in asymptomatic patients
Paucity of data suggesting any specific benefits of invasive interventions over medical therapy alone makes any CAD screening in the asymptomatic patient with diabetes mellitus highly controversial.

Statins After Stroke: What is the effect on mortality and morbidity?

Statins (cholesterol lowering drugs such as Lipitor or Crestor and others) have been shown to reduce major cardiovascular events after stroke and are considered the standard of therapy in patients with stroke. Most patients with new stroke are prescribed one of the statins when discharged from hospital. However, whether the beneficial effects of statins seen in strict clinical trials settings are also present in non-clinical trial settings remains to be seen. In other words, while it is established that statins have efficacy (work in clinical trials) it remains to be seen whether statin have effectiveness (work in usual delivery of healthcare).

The distinction between efficacy and effectiveness is an important one. A clinical trial has inclusion (and exclusion) criteria which limit enrollment to only a certain group of individuals. Patients who volunteer for clinical trials are also known to be more compliant and receptive to medical advice. Furthermore, patients in clinical trial are closely followed (and observed) and, therefore, perhaps get better care. Thus, results seen in a clinical trial setting may not hold true in the usual healthcare delivery environment where all sort of patients get drugs (or interventions), compliance may be an issue, and patients are not as closely followed. This necessitates effectiveness studies, which are not commonly performed, although thought to be quite important. Perhaps the biggest reason is that such studies are not required for a drug approval by FDA and perhaps drug companies fear that effectiveness studies may show that a particular drug (or intervention) is not as effective as shown in the clinical trial (or not effective at all).

It is then no surprise that effectiveness studies for statins in stroke (one of the commonly prescribed drug class) have not been done, that is until now. O’Brien et al report in this issue of circulation such an effectiveness study. Investigators linked data from Get With The Guidelines (GWTG)-Stroke register with the Medicare data and followed patients 2-year post-discharge for major cardiovascular events, time spent at home (out of hospital or nursing home), all cause mortality, readmissions to hospitals, and hemorrhagic stroke. Investigators report that from 2007–2011, 77,468 patients who were not taking statins at the time of admission were hospitalized with ischemic stroke. Of these 77K patients, 71% were discharged on some form of statin therapy; 31% on high-intensity statin therapy.

What they found was that the rates were lower for major adverse cardiovascular events (9% lower), mortality (16% lower), and readmission (7% lower) within two years of hospital discharge were lower for patients who were taking statins as compared with those not taking a statin. On average, patients also spent 28 more days at home. Of note, these results were adjusted for risk factors. There were no differences in rates of hemorrhagic stroke, ischemic stroke, or cardiovascular readmission by statin therapy.

Now contrast this data with the results from clinical trials of statins that showed a 20% reduction in major adverse cardiovascular events, 16% reduction in risk of ischemic stroke, and as high as 32% reduced risk of mortality. Obviously, as expected, the benefits are much larger in a clinical trial setting. This example, among others, highlights the need for effectiveness trials. Of note, this trial was funded through PCORI (a tax-payer funded program) and not by a drug company.

Life Expectancy After Myocardial Infarction

This study examines sex and race differences in long-term survival after AMI using life expectancy and YPLL to account for differences in population-based life expectancy. Investigators used the Cooperative Cardiovascular Project, a prospective cohort study of Medicare beneficiaries hospitalized for AMI between 1994 and 1995 (N = 146,743).

Investigators found that the life expectancy estimates after myocardial infarction were similar for men and women of the same race but lower for black patients than white patients.

Below is a figure from the manuscript summarizing the findings

3D Printing in Medicine

Very interesting!

With 3D printing physicians can make exact replica of a particular patient’s left atrial appendage to obtain a better fit during the appendage closure procedure. Left atrial appendage is the most common site of thrombus (or clot) formation in patients with atrial fibrillation. These clots can dislodge and go into circulation, blocking blood flow, and causing damage to the affected organs. The biggest concern (and the biggest risk) is of strokes.

Lung Function Trajectories Leading to COPD

It is commonly believed that the decline in lung function may be greater in people with already poor lung function than those with normal lung function. Now a study with a relatively large sample size shows that the decline in lung function varies among people and perhaps doesn’t depend on the baseline lung function.

Peter Lange and colleagues used three independent cohorts (Framingham, Copenhagen Heart, Lovelace Smokers) and showed that low FEV₁ in early adulthood is important in the genesis of COPD and that accelerated decline in FEV₁ is not an obligate feature of COPD.

Changing Microbiology of Community Acquired Pneumonia

Since the start of pneumococcal conjugate vaccine use for routine childhood immunization, the overall rate of invasive disease and pneumonia among adults has decreased, likely due to herd immunity. We also now have have more sensitive laboratory tests to detect pathogens responsible for pneumonia in adults. This requires an updated assessment of the incidence of pneumonia and causative pathogens.

Seema Jain and her colleagues have recently explored this question in a prospective, multicenter, population-based, active surveillance study, the Centers for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community (EPIC) study, and published results in the NEJM.

The study enrolled adults 18 years of age or older were enrolled at three hospitals in Chicago (John H. Stroger, Jr., Hospital of Cook County, Northwestern Memorial Hospital, and Rush University Medical Center) and at two in Nashville (University of Tennessee Health Science Center–Saint Thomas Health and Vanderbilt University Medical Center) from January 1, 2010, to June 30, 2012.

There were 2320 cases of pneumonia confirmed with radiographs. Quite interestingly, and in contrast to what would one expect to see, pneumonia were distributed about evenly between younger (18-49) middle (50-64) and older (>64) age groups, roughly one third in each category. Most (78%) had some underlying condition predisposing to pneumonia. Surprisingly, less than half were vaccinated with influenza or pneumococcal vaccine. Only in 38% of patients, a pathogen was detected despite using an extensive battery of laboratory diagnostics. Pathogens detected were as follows: one or more viruses in 530 (23%), bacteria in 247 (11%), bacterial and viral pathogens in 59 (3%), and a fungal or mycobacterial pathogen in 17 (1%). The most common pathogens were human rhinovirus (in 9% of patients), influenza virus (in 6%), and pneumococcus (in 5%).

At a population level, the annual incidence of pneumonia was 24.8 cases (95% confidence interval, 23.5 to 26.1) per 10,000 adults, with the highest rates among adults 65 to 79 years of age (63.0 cases per 10,000 adults) and those 80 years of age or older (164.3 cases per 10,000 adults).

The results overall reaffirm the common observation that pneumonia incidence is highest in the elderly population. Results further show that despite current diagnostic tests, no pathogen was detected in the majority of patients. The overall pathogens for pneumonia are changing with respiratory viruses being detected more frequently than bacteria.

Left Atrial Appendage Occlusion Device

Oral anticoagulants such as warfarin, factor Xa inhibitors, and direct thrombin inhibitors are the current standard of care in high-risk patients with atrial fibrillation to reduce the risk of stroke in patients with risk factors, albeit at the expense of an increase in bleed. However, the benefit of oral anticoagulation needs to be weighed against an increased risk of bleeding.

Left atrial appendage occlusion devices have the potential to change the therapy for stroke prevention in atrial fibrillation patients. ACC/HRS/SCAI have just published an overview of the literature on this topic. The overview reviews several questions related to the use of these occlusion devices. The overview starts with literature review of currently available devices (WATCHMAN, Amplatzer Cardiac Plug, LARIAT, and others) and then delves into the question of the need and requirements for care team and facilities needed for the use of such devices. This is followed by training requirement for the operator, standardization of protocols, and selection of patients for occlusion device placement. The overview is an interesting read and is available here.

Individualized Care Plans for High Utilizers of Hospital Services

There are always a small number of patients frequently visit Emergency Department (ED) and are frequently admitted to the hospital. The underlying reasons are sometimes medical conditions and sometimes are complex psychological and social issues. Formulating a care plan that is individualized for a patient with appropriate support from healthcare professionals may help to decrease utilization of healthcare services and resources by such patients.

A study published in this month’s Journal of Hospital Medicine examined the same question. Investigators formed a multidisciplinary team that developed individualized care plans integrated into electronic medical record (EMR) that summarized patient histories, utilization patterns, and management strategies. They enrolled twenty-four medically and psychosocially complex patients with the highest rates of inpatient admissions and ED visits from August 1, 2012 to August 31, 2013.

Investigators found that hospital admissions decreased by 56% (P < 0.001) and 50.5% (P = 0.003), 6 and 12 months after care-plan implementation. Thirty-day readmissions decreased by 66% (P < 0.001) and 51.5% (P = 0.002), 6 and 12 months after care-plan implementation. ED visits, ED costs, and inpatient LOS did not significantly change. Inpatient variable direct costs were reduced by 47.7% (P = 0.001) and 35.8% (P = 0.052), 6 and 12 months after care-plan implementation.

At least this one study found that individualized care plans developed by a multidisciplinary team and integrated with the existing healthcare workforce and EMR reduce hospital admissions, 30-day readmissions, and hospital costs for complex, high-utilizing patients.

Plotting Histograms in R

Histogram is probably one of the first things that we plot to look at a continuous variable. In R you can draw a histogram using its built-in ‘hist’ command. Other packages, such as ggplot2 has much more developed functions to plot histograms although one does need to learn how to use functions within those packages.

First, lets simulate data (generate fake data)
DAT = rnorm(1000, 100, 10)
Above line will generate 1000 draws from a normal distribution with a mean of 100 and standard deviation of 10

Now lets take a look at first few rows we generated
head(DAT)

Lets look at the summary of the data
summary(DAT)

Note: You may get different data every time as we have not set a seed but that is not important at this time.

Now draw first histogram
hist(DAT)

Add color to the histogram
hist(DAT, col="blue")

Now lets take control on the number of histogram bars
hist(DAT, col="blue", breaks=25)

Change Y-axis from frequency (which is default) to density
hist(DAT, col="blue", breaks=25, probability=TRUE)

Add labels to the histogram
hist(DAT, col="blue", breaks=25, probability=TRUE,
     main="My Pretty Histogram",    ### For title of the figure
     xlab="My Fake Data")           ### For x-axis label

Add a dark green-color  kernel density curve to the plot
lines(density(DAT), col="darkgreen", lwd=2) 

Add a red-color normal density curve to the plot
curve(dnorm(x, mean(DAT), sd(DAT)), add=TRUE, col="red", lwd=2) 

Below is similar to what you should expect to get:

Identifying and Developing a Research Question

Below are some of the resources that may be helpful in learning how to develop a research question

1. Coming up with a research question [Kinmond 2012]

2. Developing great research questions [Lipowski 2008]

3. When is a research question not a research question? [Mayo 2013]

Installing Packages in R

R has thousands of packages that extend its use to almost every arena of research. It is highly likely that you will not need most of these packages but it is also likely that you will need several of them (perhaps from 5 to 20) depending on what you plan to do. Most of these packages are available on the the CRAN website.

http://www.cran.r-project.org/web/packages/available_packages_by_name.html

Bioconductor is another source of R packages for bioinformatics-related research packages can be downloaded from its website.

http://www.bioconductor.org/packages/release/bioc/

To use a package, there are two steps:

First Step: Download and Install a Package – you can download a package to a local directory and install it from there using drop down menu OR you can directly install it from the CRAN repository. Depending on the R GUI user interface that you use, the exact steps may be slightly different. Often, first you have to specify which mirror you want to use; chose a mirror that is geographically closer to you for faster downloads. Then you can chose a package from the package list.

I use RStudio GUI. In Rstudio, click on the tab labeled ‘Packages’. If this tab is not visible, press Ctrl+7 and the tab will become visible (usually in the right lower quadrant of the window). From there you can chose install, then type in the name of package (if multiple packages, enter package names separated by space or a comma). Make sure that ‘install dependencies’ box is checked. Make sure that the correct repository and installation location are selected. Then click Install. You can also chose to use installation command directly from the console; the command below will install ggplot2 package:

install.packages("ggplot2")

Note that you need to install packages only once

Second Step: Loading a Package – Installing a package makes it available for later use but packages are not automatically uploaded during a session. Once you have installed a package, you will need to load that package when you need it during a session. To load a package use the function ‘library()’. the following command will load the package ggplot2.

library(ggplot2)

Some may like to use ‘require()’ function instead of ‘library()’. However, see this post for the differences between the two and why one should prefer ‘library()’ over ‘require()’

Personally, I try to load all needed packages at the beginning of a script. However, this strategy may not work if there is an overlap in the names of functions between two packages and you may see a warning “The following objects were masked from ‘package:xyz’:”. 

Some other useful commands to know

.libpaths() # – will give you location of library for packages
library() # – will show you all installed packages
search() # – will show you currently loaded packages

Some Thoughts About Clinical Research

Clinical research requires a wide range of skills. These skill include the ability to work with a wide range of people, to lead teams with people from wide and vastly different backgrounds, to design appropriate studies, to ask right questions, to understand research methods specific to the study question, to develop in-depth content expertise in the area of research focus, to get funding for research projects, to present study results at national meetings, to write manuscripts for publication in peer-review journals, and so on and so forth.

A fundamental skill for a researcher is the ability to knit together the conceptual framework for a study (theory) with appropriate measurement, with the result either supporting or opposing the conceptual framework. The theory should be based on the most current state of knowledge, the data collected should have the ability to test the theory, the statistical models should reflect both the conceptual structure hypothesized to have given rise to the data and the nature of collected data, and the inferences should be based on the data and the tested statistical models. This process is not linear, rather it is a loop in which theoretical aspects inform the collection of data and results of the data analyses help in refining the theory, which generates more testable hypothesis, additional data collection, and so on.

Most research is probabilistic, as opposed to deterministic. In other words, the results we obtain are not always certain; we have to include uncertainty in our analyses and expect some uncertainty in our results and inferences. Thus, we have to accept that our results are unlikely to be laws governing the system we plan to study and more likely to be an approximation of what we expect to find in the real world, with some uncertainty. There are many reasons and sources of this uncertainty some of which can be addressed while others may still be there despite our best attempts.

A researcher should determine whether the interest of research is to build inferences at population level or at the level of individuals unit (often a patient in clinical research). The study design, data collection and analysis, and the inferences may be quite different depending on what is the object of our interest. While we study individuals, our results usually address inferences at population level. In general, it is much easier to predict about the response at a population level, that is on an average, individuals with higher body mass index (say >30) will have higher blood glucose than (say) 126mg/dL. However, it is much difficult to predict with certainty how likely a particular individual with a BMI>30 is to have higher blood glucose level than 126 mg/dL. For a predictor to work well at an individual level, among other things effect size needs to be quite large.

Another important concept is that of causality. While we often have a conceptual model in our mind that A is caused by B, it may be quite difficult to prove except perhaps in a clinical trial setting. There are several factors that can increase the likelihood that the direction of cause and effect in our conceptual model is correct, such as temporality and biological plausibility.  However, often there remains a possibility that B is in fact caused by A or that some other unknown (or unmeasured) factor, C, may be responsible for both A and B. Hence, we often claim an association or correlation between A and B and not causality.

Starting to work with R

There may be some who have just started working with R after someone convinced them that R is the way to go. For those souls, it may be difficult to get started quickly. Below are some of the steps to use to start working with R

Step 1: Go to the CRAN webpage and download the version of R that is appropriate for your operating system - http://cran.r-project.org/

Step 2: Install R

Step 3: Download a GUI for R – While R comes with a GUI, other GUIs are much better. My favorite is RStudio, To download RStudio, go to RStudio website and download the version that is appropriate for your operating system - http://www.rstudio.com/products/rstudio/download/

Step 4: Install RStudio (or a GUI of your choice).

Step 5: Start using RStudio (or GUI of your choice)

That’s it – Good luck!

Fractional Flow Reserve–Guided PCI for Stable CAD

The utility of PCI in stable CAD is unclear. Fractional flow reserve (FFR) may be used to stratify patients between those who will benefit from PCI from those who will not.

A randomized clinical trial published in NEJM examined this question. Patients with FFR<0.8 were randomized to PCI or medical therapy. Although the primary endpoint included a soft endpoint (revascularization) there was significant decrease in the primary endpoint among patients who underwent PCI (8.1 vs 19.5%). Further, the hard endpoints (death or nonfatal myocardial infarction) were also reduced significantly in FFR patients (4.6% vs 8.0%). Quite interestingly, the individuals with FFR greater than 0.8 met primary endpoint as often as those with FFR<0.8 and PCI (8.1 vs. 9.0%) although this was not a direct comparison group.

Interesting results! ……… Perhaps practice changing?

Thunder and Spark–Cluster computing made easy (a little)

Here it is

Epiviz–an interactive visual tool for genomics data

Epiviz is an interactive visualization tool for functional genomics data. It supports genome navigation like other genome browsers, but allows multiple visualizations of data within genomic regions using scatterplots, heatmaps and other user-supplied visualizations.

Cant Imagine this can happen

Even in this day and age when almost everything is available on internet how can this happen? Perhaps no one who was hiring or promoting this dude knew how to use internet. Someone can lie about his/her qualifications (such as getting a PhD) and no one checks before hiring for assistant or associate professor? Shouldn’t folks at NUS, WVU and VCU be ashamed of their gross negligence?

Maximizing Public Data Sources for Sequencing and GWAS Studies

An interesting presentation

CONFIRM-HF - Replete Iron in Heart Failure Patients?

Findings from the CONFIRM-HF (Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure) trial, point to a simple and safe solution for heart failure patients with iron deficiency who can experience significant and sustainable improvements in functional capacity and quality of life as well as reduced risk of hospital admission for worsening heart failure by iron supplementation.

CONFIRM-HF is a double-blind, placebo-controlled trial, which enrolled 304 stable, symptomatic heart failure patients from 41 sites across nine European countries. All patients had iron deficiency, defined as a serum ferritin level < 100 ng/mL, or between 100 and 300 ng/mL with transferrin saturation < 20%. Subjects were randomized to receive either intravenous iron (n=152), given as ferric carboxymaltose solution (FCM), or a normal saline placebo (n=152), for 52 weeks. Completion of the six-minute walk test (6MWT) was required at baseline, and the primary endpoint of the study was improvement in this test at week 24.

Compared to placebo-treated subjects, those treated with FCM completed 33 extra meters in the 6MWT at week 24 (p=0.002), 42 extra meters at week 36, and 36 extra meters at week 52 (both p<0.001) and the improvement was seen in all subgroups. Despite the reduction in hospitalizations among FCM-treated patients, the number of deaths was similar in both groups, suggesting a one-year follow-up may not be long enough to detect differences in mortality.
Adverse events were mild, and occurred at a similar rate in both groups.

A New Drug For Heart Failure

ACE inhibitors are standard of therapy in patients with heart failure as clinical trials have shown mortality benefit with these drugs. A trial published in NEJM compared a new drug LCZ696 with enalapril (an ACE Inhibitor) and found this new drug to far better.

This trial randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy.

The trial was stopped early (after a median follow-up of 27 months) because there was clear evidence of benefit of LCZ696 over enalapril. The primary outcome (a composite of death from cardiovascular causes or hospitalization for heart failure) had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001).

The incidence and type of adverse effects were different between the two drugs; the LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema while enalapril group have higher proportions with renal impairment, hyperkalemia, and cough.

LCZ696 is an investigational combination drug consisting of two antihypertensives (blood pressure lowering drugs), valsartan and AHU-377, in a 1:1 mixture. It is being developed by Novartis. The combination is often described as a dual-acting angiotensin receptor-neprilysin inhibitor although the two effects are achieved by two different molecules. AHU-377 is a prodrug that is activated to LBQ657 by de-ethylation via esterases.LBQ657 inhibits the enzyme neprilysin, which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure lowering peptides that work mainly by reducing blood volume.

On the financial side, projections on peak sales from the company's own bullish $2 billion to $5 billion. The highest estimate is by Deutsche's awestruck of $10 billion while the lowest is by EvaluatePharma which pegged nearer-term 2020 sales at a much more modest $1.3 billion.

Colchicine - Postpericardiotomy Syndrome - Postop AFib

Not surprisingly, increased morbidity and perhaps increased mortality, is associated with postpericardiotomy syndrome as well as post-operative development of atrial fibrillation and pericardial and pleural effusions. Colchicine may prevent these complications and COPPS-2 trial looked at this possibility.

This trial was reported in JAMA and also presented at ESC

The results were as below:

PRIMARY ENDPOINT: “The primary end point of postpericardiotomy syndrome occurred in 35 patients (19.4%) assigned to colchicine and in 53 (29.4%) assigned to placebo (absolute difference, 10.0%; 95% CI, 1.1%-18.7%; number needed to treat = 10).

SECONDARY ENDPOINT: “There were no significant differences between the colchicine and placebo groups for the secondary end points of postoperative AF (colchicine, 61 patients [33.9%]; placebo, 75 patients [41.7%]; absolute difference, 7.8%; 95% CI, −2.2% to 17.6%) or postoperative pericardial/pleural effusion (colchicine, 103 patients [57.2%]; placebo, 106 patients [58.9%]; absolute difference, 1.7%; 95% CI, −8.5% to 11.7%), although there was a reduction in postoperative AF in the prespecified on-treatment analysis (placebo, 61/148 patients [41.2%]; colchicine, 38/141 patients [27.0%]; absolute difference, 14.2%; 95% CI, 3.3%-24.7%).

ADVERSE EVENTS: “Adverse events occurred in 21 patients (11.7%) in the placebo group vs 36 (20.0%) in the colchicine group (absolute difference, 8.3%; 95% CI; 0.76%-15.9%; number needed to harm = 12), but discontinuation rates were similar”.

Platelet Glycoprotein IIIa and Aspirin Resistance

Aspirin is the mainstay of treatment for the prevention of cardiovascular disease. It acts by irreversibly inhibiting COX1 enzymes and hence blocking arachidonic acid-thromboxane pathway. Due to lack of a nucleus, platelets cannot generate new COX1 and hence COX1 is inhibited for the lifetime of platelets (8 days). Aspirin treatment results in marked decrease in the excretion of urinary metabolites of thromboxane; the residual excretion is thought to be of endothelial origin where presence of nucleus results in formation of new COX1.

Despite adequate aspirin therapy, a significant number of individuals continue to have higher platelet reactivity and incomplete inhibition of platelet function. Such individuals are also at increased risk of future cardiovascular events. However, the underlying mechanisms that result in higher residual platelet reactivity after aspirin treatment are unclear and are being extensively explored by several researchers.

To identify mechanism of aspirin resistance, this study examined the differences in proteome of 2 aspirin resistant and 4 aspirin sensitive individuals and found that the levels of glycoprotein IIIa were higher in aspirin resistant individuals than in those without aspirin resistance.

Due to small sample size, it is difficult to rule-out the possibility of a type I error, however, considering the role of glycoprotein IIIa in platelet biology, it is conceivable that protein may play a role in aspirin resistant although exact mechanism remains unknown.

Benefits of Aspirin Use in the General Population

Aspirin is perhaps the most commonly used drug world-wide for various ailments. Its prophylactic use in secondary prevention of cardiovascular diseases is well-established, however its use for cardiovascular disease prophylaxis in primary prevention has not been as clear. In particular, some recent meta-analysis has raised concern that aspirin use may not be beneficial for primary prevention of cardiovascular diseases. In support of a role of aspirin use in general population, a systematic review recently concluded:

“For average-risk individuals aged 50–65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, myocardial infarction or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period”

In other words, aspirin use is beneficial for both cardiovascular and cancer standpoint, its takes three years to see a beneficial effect, and effect lasts long after aspirin use has been discontinued.

Platelet Diameters in Inherited Thrombocytopenia

An interesting article providing a systematic evidence for what is well-known but not reported in a systematic manner.

“To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters………….. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size….”

iRegulon: From a Gene List to a Gene Regulatory Network Using Large Motif and Track Collections

Identifying master regulators of biological processes and mapping their downstream gene networks are key challenges in systems biology. iRegulon is a software that implements a genome-wide ranking-and-recovery approach to detect enriched transcription factor motifs and their optimal sets of direct targets. The software can be obtained from this website

 

Circleator: Flexible Circular Visualization of Genome-Associated Data

Came through this interesting package which builds graphs similar to Circos but just a little easier

“Circleator is a Perl application that generates circular figures of genome-associated data. It leverages BioPerl to support standard annotation and sequence file formats and produces publication-quality SVG output. It is designed to be both flexible and easy to use. It includes a library of circular track types and predefined configuration files for common use-cases, including: 1. visualizing gene annotation and DNA sequence data from a GenBank flat file,
2. displaying patterns of gene conservation in related microbial strains,
3. showing SNPs and indels relative to a reference genome and gene set, and
4. viewing RNA-Seq plots.”

Greater Collagen-Induced Platelet Aggregation Following Cyclooxygenase 1 Inhibition Predicts Incident Acute Coronary Syndromes

Platelets have several pathways that initiate aggregation such as thrombin-, collagen-, thromboxane-, and ADP-mediated pathways. Individuals vary widely in their ability to have platelet aggregation through each of these pathways. Furthermore, this variability is not correlated. In other words, an individual may have low aggregation though one pathway but may have high aggregation through another pathway. This phenomenon may be more important when we try to measure platelet aggregation the laboratory to assess whether there is increased risk of in vivo platelet aggregation (and hence cardiovascular events).

Collagen is one of the first agonists that initiates platelet aggregation at the site of vessel wall injury. Therefore, examining an association of collagen-mediated platelet aggregation with subsequent cardiovascular events makes sense. Moreover, if we can decrease variability in platelet aggregation by blocking one or another pathway, we may be better able to assess activation through collagen pathway.

Aspirin is commonly used for prevention of cardiovascular disease and works by inhibiting thromboxane-pathway an dis very effective in completely inhibiting activity through this pathway. Thus aspirin can be used to inhibit variability through one pathway and effect of collagen can be studied with fewer interactions. We followed the same logic in this paper where we examined platelet aggregation after 2-week aspirin therapy in healthy individuals. Most of these individuals did not use aspirin after the 2-week study period. During follow-up increased collagen-mediated platelet aggregation was significantly associated with acute coronary syndrome.

“After COX1 pathway inhibition, collagen-induced aggregation was significantly greater in participants with ACS compared with those without (29.0 vs. 23.6 ohms, p < 0.001). In Cox proportional hazards models, this association remained significant after adjusting for traditional cardiovascular risk factors (HR = 1.10, 95%CI = 1.06-1.15; p < 0.001).”

The Science Publishing Complex – <1% publish 42% of all papers

There are not as many successful scientists as we think there are – most are just trying (or leaving).

“Using the entire Scopus database, we estimated that there are 15,153,100 publishing scientists (distinct author identifiers) in the period 1996–2011. However, only 150,608 (<1%) of them have published something in each and every year in this 16-year period (uninterrupted, continuous presence [UCP] in the literature). This small core of scientists with UCP are far more cited than others, and they account for 41.7% of all papers in the same period and 87.1% of all papers with >1000 citations in the same period.”

The End of HDL-raising Therapies?

Patients with cardiovascular disease are at increased risk of subsequent events than individuals without a history of cardiovascular disease despite optimal medical management. Various strategies has been proposed to decrease this increased risk among them increasing HDL.

The HPS2-THRIVE trial examined this question by randomly assigning almost 26,000 individuals with established vascular disease to either placebo or Naicin+laropiprant; a combination that should raise HDL cholesterol. Participants were followed for a median period of 3.9 years. Individuals randomized to the treatment arm had lower LDL (about 10 mg/dL) and higher HDL (about 6 mg.dL) than those who were randomized to placebo. During follow-up, there was no difference in the incidence of major cardiovascular events between the two groups13.2% vs. 13.7%; p = 0.29). On the other hand, individuals randomized to the treatment arm had increased incidence of adverse events such as poor diabetes control or increased incidence of new diagnosis of diabetes.

For now, this trial, puts to rest the use of niacin for decreasing the risk of cardiovascular disease. However, it also raises important questions about the interest in the development of pharmacological therapies directed towards raising HDL-cholesterol. It further questions our current understanding of the role of HDL in the pathogenesis of cardiovascular diseases.

Some interesting articles

Sticky Platelet Syndrome: History and Future Perspectives
in Seminars in thrombosis and hemostasis

The relationship between platelet to lymphocyte ratio and the clinical outcomes in ST elevation myocardial infarction
in Blood coagulation & fibrinolysis

Detection of platelet microRNA expression in patients with diabetes mellitus with or without ischemic stroke
in Journal of Diabetes Complications

Aspirin may modify tumor microenvironment via antiplatelet effect
in Medical Hypothesis

Some interesting articles

 

Optimizing current treatment of gout
in Nature Reviews Rheumatology

 

Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones
in Nature

 

Health eHeart: A Framingham Study for the Social Media Era?
An interesting concept