US Federal Government Shutdown Freezes NIH Operations

Yes. You read correctly. The United States Federal government entered a shutdown on October 1, 2013 and for 17 days. The first question that came to my mind “Can they even do that?”. Believe it or not, yes they can! Setting aside the complex political fight behind that (generally because of President Obama healthcare law, aka ObamaCare), let me walk you through what relates to us; biomedical researchers.

Photo credit: originally published on Cambria Press

The Washington Post estimated that 800,000 federal employees were indefinitely furloughed. However, 1.3 million "essential" federal workers, 1.4 million active-duty military members, 500,000 Postal Service workers, and other employees in independently-funded agencies were required to report to work with no expectation to receive their salaries.

As a result, the NIH released a statement that all its operations, including grant submissions, reviews and funding, have been suspended due to the lapse in federal funding. The NIH resumed its operations on October 17, 2013.

This reminds me with an editorial published in JAMA earlier this year by Dr. Ezekiel J. Emanuel, Vice Provost for Global Initiatives and chair of the Department of Medical Ethics and Health Policy at the University of Pennsylvania. Dr. Emanuel predicted within the lines of his editorial what we face now.

Dr. Emanuel summarizes four factors that contribute to the “erosion of support for the NIH”. These include:

• First, politicization of science by losing the bipartisan agreement that long existed in the US.
• Second, disappearance of strong Congressional champions of the NIH, most importantly, John Porter (R, IL – Retired), Arlen Specter (D, PA – Died), and Ted Kennedy (D, MA – Died).
• Third, the congress may have thought that NIH funding has been sorted out after the 2003 doubling of its budget.
• Fourth, the continuous increase in the US federal budget deficit over $1 trillion makes the case harder to justify that NIH funding for biomedical research should be a top priority.

Dr. Emanuel proposes three solutions that could improve the dire NIH funding situation.

• First, pro-NIH congressional members need to be identified, educated, and cultivated, to lead the fight for increasing funding for biomedical research.
• Second, researchers have to do a better job of explaining the value of biomedical research, and stop promising cost reductions.
• Third, physician researchers should focus on efficient delivery of patient care, rather than just increased profit from clinical services. This will make the health-related expenditures must stop increasing faster than GDP, allowing more room to ask for more NIH funding.

 The editorial closes with:

“Most importantly, the NIH and the larger biomedical research community need to direct their considerable talents and resources to developing biomedical technologies that are not just “incredibly exciting” but also cost lowering and value enhancing. Many tremendous triumphs of NIH research, such as the Haemophilus influenza type B vaccine, did just that.”

Well, This says it all!

The Largest Meta-analysis on Global AKI Incidence

This month, the Clinical Journal of the American Society of Nephrology (CJASN) published a meta-analysis on the epidemiology and global incidence of acute kidney injury (AKI) last month. 

Dr. Bertrand L. Jaber and his colleagues from Tufts University School of Medicine included 312 published cohort studies (between 2004 and 2012) with 49 million adult and pediatric patients, from over 40 countries across all continents.

Incidence of AKI:

• The pooled incidence rate of AKI was 10.7% using all the 312 studies. However, in a subgroup analysis of 154 studies that used a KDIGO-equivalent AKI definition, the pooled incidence rate of AKI was 23.2%.
• The highest pooled incidence rate of AKI was found in ICU to be 37%, followed by cardiac surgery 24%.
• The pooled incidence rate of AKI was higher in countries south versus north of the Equator (27% vs 22%, respectively), and higher in countries that spent more than 10% of its GDP on total health expenditure vs those countries that spend less than 5% (25% vs 14%).

Incidence of AKI-associated mortality:

• The pooled incidence rate of AKI-associated mortality was 23%.

Ancillary findings:

• There were 269 studies of adults, 42 studies of children, and 1 study combining adults and children.
• There were 62% retrospective cohort studies, 35% prospective cohort studies, and 3% post hoc cohorts derived from clinical trials.
• Sample size of individual studies on adults ranged from 500 to 12 millions, and on children varied from 64 to 60 thousands.
• The mean age ranged from 23 to 80 years for adults and from 0 to 13 years for children.
• Studies from high-income countries represented 87% of the studies included in this meta-analysis

Comment:

This is a landmark meta-analysis in the area of AKI epidemiology. It is the first and largest meta-analysis of AKI incidence that include both adults and pediatric patients from allover the world. Beside the surprising findings that AKI occurs around the world, there has been a disparity in the representation of certain countries in this meta-analysis, simply due to the lack of published evidence from these countries. The findings of high AKI incidence in high-income countries warrant further investigations to identify the causes and develop solutions. However, I believe that the low incidence from countries that spend less than 5% of their GDP on health expenditure could be false. This could be attributed to the underdiagnosis of AKI from lacking nephrology-trained physicians. Besides, lack of scientific publications in this area could contribute to the potentially false low incidence, in my opinion.

Jaber et al conclude:

“…discussions should encourage providers to design better hospital-based health care delivery systems that focus on the prevention, early detection, and treatment of AKI, improve patient safety, and ultimately, preserve kidney health and well-being while mitigating the long-term costly burden of CKD."

Chronic Kidney Disease Definition Controversy

Probably the most important item in the checklist of a clinician, an epidemiologist or a researcher is the “definition of disease”. What are the criteria that make this individual labeled with disease A, and this individual isn’t? These criteria are grouped into “the definition”.

There has been a considerable variation in definitions of various diseases across the history of medicine. Some of these variations are attributed to the reason for defining the disease (patient care or research purposes). Variations also existed because of the use of early detection biomarkers or advanced imaging modalities. The more progress we, the epidemiology researchers, achieve in providing clinicians ways for early disease detection, the more “cases” are expected to be detected early, potentially saved, and easily treated. This means expanding the “definition of the disease” to encompass more people who potentially have the disease, or have the disease in very early stages. From an epidemiologic standpoint, this will lead to an increase in the disease prevalence.

Although clinicians, epidemiologists and researchers are expected to view this as a privilege, many have criticized that expanding the definitions leads to overdiagnosis. This is discussed in a recent article published in the British Medical Journal on expanding the definition of chronic kidney disease (CKD). Ray Moynihan, the lead author on this article, and his colleagues overviewed the story of CKD definition, the rationale behind the 2002 NKF KDOQI ClinicalPractice Guidelines, and then discussed in details the issue of CKD overdiagnosis.  

To begin with, these guidelines set the CKD definition to be either estimated glomerular filtration rate of 60 ml/min/1.73 m2 for ≥3 months (presence of impaired kidney function), or albuminuria ≥3 months (presence of kidney damage). About 14% of the US adults and about 17% of the Australian adults were labeled as CKD patients, as a result of this new definition.

The authors of the BMJ article present the evidence of overdiagnosis. Of the evidence they presented, they conclude that without adjusting to age and gender, about half of the individuals over 70 years old will be labeled with CKD. Schaeffner and colleagues from Germany published a paper in the Annals of Internal Medicine last year presenting two novel equations to estimate kidney function in persons aged 70 years and older, and calibrating their equation with Iohexol plasma clearance measurement as gold standard. They found that with the measured GFR, 47.9% of their sample has GFR less than 60 mL/min per 1.73 m2. Using the NKF KDOQI definition, these individuals have CKD.

However, scientists against the use of eGFR threshold of <60 ml/min/1.73 m2 as a cutoff for CKD definition question whether such CKD definition will have any real implications on risk assessment and clinical care of patients with cardiovascular disease. Additionally, the authors cited evidence that suggests that because of the variability of the eGFR, diminished kidney function as eGFR <60 ml/min/1.73 m2, needs to persist for at least 12 months to diagnose CKD. As a consequence, this could reduce the prevalence of CKD stage 3 by 37%.

Just last year, the US Preventive Services Task Force (USPSTF) published a statement on the Screening for chronic kidney disease. Despite finding no evidence on the presence of direct harms of screening for CKD, it suggested that there is “potential harms of screening include adverse effects from venopuncture and psychological effects of labeling a person with CKD as a result of a false-positive test”. As a result of overdiagnosis, increased referral to nephrologists has been also observed.

The case is still open and the authors state that “it needs further professional scrutiny and public awareness”. Patient care should be individualized when the treating physicians receives the eGFR result below 60 ml/min/1.73 m2 or albuminuria, taking into account the patient’s age, gender, and existing comorbidities. Needless to say, the test should be repeated after 3 months.

The authors conclude:

“Clinicians should be careful not to apply disease labels to the many older people whose eGFR falls within the definition of chronic kidney disease but who are at very low risk of developing clinical problems… It is in everyone’s interest to find the best way to maximise prevention of kidney disease and its consequences while minimising the risks and cost of overdiagnosis.”

More on Funding of Biomedical Research

In this post, I tap on a burning issue that is immensely important to people like me who are working full time in biomedical research; funding. Despite the hurdles it faces to improve care, clinical medicine generates direct income (and profit) through the patient care it delivers. Such income pays physicians, nurses, hospital teams, overheads etc… Unlike clinical medicine, biomedical research is mechanism that requires tons of money, but it is always viewed as a national investment for future economic growth.

The National Institutes of Health (NIH), the largest funding organization of biomedical research in the world, describes the impact of its work on US economy, and states that:

It directly supported almost half million jobs in medical research in 2012
For every $1 of NIH funding, about $2.21 is generated in local economic growth.
Let’s look at just one example. The U.S. government’s $4 billion investment in the Human Genome Project spurred an estimated $965 billion in economic growth from 1988-2012; a 178-fold return on investment, after adjusting for inflation.

NIH isn't the only US governmental agency that funds biomedical research. Other major agencies include Department of Defense, Department of Homeland Security, and Department of Agriculture, among many others.

However, who decides the dollar amount to be spent by these agencies is the legislative arm in the US; the Congress. Due to the major budget cuts in 2010:

NIH budget was decreased by ~14%
Department of Defense budget was decreased by ~12%
Department of Agriculture budget was decreased by ~20%
What is very shocking is that the Department of Homeland Security budget for biodefense was almost shut down, and decreased by ~91%.

A striking example showing the projected difference between healthcare spending on Parkinson’s Disease versus the research and development (R&D) spending on Parkinson’s Disease is shown in the below figure. While the current funding limits are maintained, the healthcare cost of the 1.5 million Americans with Parkinson’s Disease, with annual incidence of 60k new cases, will jump from $8 billion to $18 billion per year. 

Figure adapted from 10th annual Investment in Research 2012 report by Research!America.

Federal spending on R&D doesn't only support direct biomedical research in the US. In addition to support training programs (predoctoral, doctoral, and postdoctoral levels) and research centers, it also supports research globally through USAID and the NIH’s Fogarty International Center.

More detailed figures can be found in 10th annual Investment in Research 2012 report by Research!America. 

Caloric Content in Restaurant Meals is in Excess of What We Actually Need

To follow up on my latest post, I read another paper was published simultaneously with the paper I discussed in JAMA Internal Medicine studied the food served in restaurants from a different angle. Investigators from the Human Nutrition Research Center on Aging (HNRCA) of Tufts University in Boston studied the energy content in the most commonly purchased foods in a random sample of independent and small-chain restaurants.

Inclusion criteria for a restaurant were: to be a “sit-down” restaurant, within 15 miles from downtown Boston, have a online menu with no nutrition labels. Restaurants were classified according to the number of employees (small <10 employees, large ≥10 employees), and the type of food served (Mexican, American, Chinese etc…), and then randomly selected according to these two categories. The research team led by Dr. Susan Roberts, The director of the Energy Metabolism Laboratory at the HNRCA, selected the 5 most popular entrée choices and their standard side dishes from each restaurant. They included 157 meals representing 42 meal categories from 9 restaurants in the present study.

Due to my inexperience in nutrition labeling and nutrition research methods, the next part is very interesting to me. The authors used the Bomb Calorimeter to estimate the energy content in each meal using the kilocalorie (kcal) as the measuring unit. The food must be grounded into fine powder. I found the following very interesting (and fun) interactive flash video explaining how the Bomb Calorimeter works. 

I embedded this video from its original source in McGraw-Hill.

Back to the paper! So the analysis of the energy content in the sample meals offers interesting results. To set the stage, the authors used the US federally-referenced daily energy requirement (as stated in the CFR Title 21, Volume 2§101.9(d)(9)(i)) to compare their results to it. This value is 2,000 kcal per day.

The mean energy content of all food categories of all the samples and all restaurants was 1327 kcal, which is already >66% of daily energy requirement reference value. The Italian meal categories had the highest mean energy content of 1755 kcal, and the Vietnamese meal categories had the lowest mean energy content of 922 kcal. Interestingly, some of the sample meals provided even more than 100% of the daily energy requirement. This includes; the Mexican Classic Nachos providing 2165 kcal, and the Italian Fettuccini Alfredo [yummy!!] providing 2270 kcal. The authors also found that 75% of individual sampled meals contained at least 50% of the daily energy requirement.

Overall, this study provides overwhelming evidence that “dining out” entails consuming food with energy content more than what our bodies need. One should pay more attention to how many calories are in the meals ordered in restaurants, regardless of its type (fast-food, small chain, or even independent), or cuisine. But this can’t be done without data. Restaurants should provide nutrition labels on their menus to help diners decide what to eat, and advocate for healthy choices.

The study authors concluded:

A national requirement for accurate calorie labeling in all restaurants may discourage menus offering unhealthy portions and would allow consumers to make informed choices about ordering meals that promote weight gain and obesity.

PS: If you are interested to know how many calories your need based on your BMI and Physical Activity Level (PAL), check this link from the Food and Agriculture Organization of the United Nations. 

Soduim Content in Foods is Almost Constant!

No doubt that sodium is an important risk factor for hypertension. The American Heart Association estimates that there are 78 million adults in the US (1 in 3) have high blood pressure. In a workshop organized by the National Heart, Lung, and Blood Institute (NHLBI) on sodium and blood pressure, the report stated

“There is an abundance of scientific evidence demonstrating a direct relationship with sodium intake and blood pressure”.

I came across an interesting article published in JAMA Internal Medicine this week titled “Changes in Sodium Levels in Processed and Restaurant Foods, 2005 to 2011”. Dr. Stephen Havas from Northwestern University Feinberg School of Medicine, and his colleagues collected the sodium content data in processed food from the nutrition facts label in 2005, and recollected the same data for the same food products in 2011.

The main finding with their analysis is that the sodium content in the 402 processed food products declined by only 3.5% over 6 years. On the other hand, the sodium content in 78 fast-food restaurants’ products increased by 2.6%. Table 1 in their paper shows that Caesar salad dressing and Turkey breasts are the top 2 food categories, with highest sodium content in 2005 to 2011. Canned tuna fish, canned tomato, sliced turkey breast, and vegetable soup had the highest decline of the sodium content by about 22%, from 2005 to 2011. For the rest of the processed foods, the sodium content either remained constant or changed by ±2%.

Among the restaurant foods, the sodium content in the French fries increased by 27% from 2005 to 2011. Cheese pizza’s sodium content increased by about 12% in the same period.

The authors outlined in Table 3 the names of some companies that committed to reduce sodium levels in their products. For example, the Domino’s Pizza committed to decrease the sodium content in the smart pizza slice for schools by a third. Wal-Mart committed to reduce sodium by 70% in fresh steaks and roasts.

The authors concluded that 

“It is clear from this analysis that reductions in sodium content in both processed and restaurant foods are both inconsistent and slow”

I think it is a time for the local, state and federal government to look into new ways to enforce sodium content reduction in processed and restaurant foods to alleviate the burden of preventable diseases (like hypertension). This could be similar to what Mayor Michael Bloomberg did by prohibiting the sale of soda cans more than 16 ounces. Although there has been a resistance against the implementation of this bill, public health advocates has long way to go. 

Eating Fish is Associated with Decreased All-Cause Mortality in Older Adults

Mozaffarian and his colleagues published a paper recently in the Annals of Internal Medicine analyzed data from 2692 U.S. adults aged 74 years (±5 years) without prevalent cardiovascular diseases at baseline, who participated in the National Heart, Lung, and Blood Institute (NHLBI)-funded cohort, The Cardiovascular Health Study (CHS). The investigators measured the blood circulating levels of 3 types of long-chain omega-3 polyunsaturated fatty acids (omega-3 PUFAs); eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). These were measured from the blood that was collected from the participants in 1992. They then followed them longitudinally for 16 years (1992 through 2008) to evaluate the relationship with total and cause-specific mortality and incident fatal or nonfatal CHD and stroke.

The authors found that the individual levels of EPA, DPA, and DHA, and their total levels (omega-3 PUFA) were associated with lower total mortality across three robust models of adjusted Cox proportional hazards models (age, gender, various demographic and co-morbid conditions, and dietary factors):

       The participants in the higher quintile of the total omega-3 PUFAs had 27% lower risk 

       The participants in the higher quintile of EPA had 17% lower risk 

       The participants in the higher quintile of DPA had 23% lower risk

       The participants in the higher quintile of DHA had 20% lower risk

All results were statistically significant with narrow 95% confidence internals.

For cause-specific mortality, and using the same adjustment models of the total mortality risk data, total omega-3 PUFAs, and most of the individual levels of the three subtypes, were associated with cause-specific mortality. Total omega-3 PUFAs was associated with: 

       35% lower risk from cardiovascular mortality

       40% lower risk from coronary heart disease mortality

       45% lower risk from arrhythmic coronary heart disease (CHD) mortality

       28% lower risk from non-arrhythmic CHD mortality

       40% lower risk from stroke mortality

       28% lower risk from total fatal and nonfatal CHD mortality

       17% lower risk from nonfatal myocardial infarction mortality

       25% lower risk from total fatal and nonfatal stroke mortality

       37% lower risk from Ischemic stroke mortality

This data strongly suggests that fish consumption or fish oil supplementation would reduce both total mortality and cause-specific mortality in older adults. The steepest dose-response relationship between the circulating blood levels of omega-3 PUFAs and the decreased risk came from as low as 400 mg per day dietary intake, or two servings of fatty fish per week. This will lead to an average increase of about 2 more years of life in those with higher levels compared to those with lower levels.

My opinion:

This conclusion is supported by the robust statistical analyses with adjustment to many confounders, as well as a quantification of the omega-3 PUFAs rather than the amount of fish intake from Food Frequency Questionnaires (FFQ) or similar tool. Despite some limitations in this paper, it is a landmark paper in supporting increased fish intake to decrease the risk of mortality in older adults.