Tag Archives: obesity

Can Belly Fat Cause Cancer?

Ammu Dinesh and Claire Viscione, National Center for Health Research

Belly fat is common among men and women. However, when a person’s body shape looks more like an apple than a pear, that could increase their likelihood of developing cancer. 

More than two-thirds of adult Americans are overweight or obese.1 Most people know that obesity increases the risk of diabetes, heart disease, and high blood pressure. But did you know that being overweight increases your chances of developing cancer, and that having an “apple” body shape due to belly fat can increase your chances of developing cancer even if you are not overweight?

Why is belly fat dangerous?

Whether your body fat is located at your waist (giving you an apple shape) or hips (giving you a pear shape) makes a difference to your health. Women tend to gain more belly fat as they get older. Regardless of their weight, white, black, and Latina women with a waistline measurement of 35 inches or more have higher health risks. This is also true for Asian women with a waistline of 31 inches or more. Although it is important to get rid of excess fat in general, belly fat is the most threatening to your health.

Physicians use often use body mass index (BMI) to estimate whether you are overweight or obese. However, determining your waist circumference is just as important. Even if you are not overweight or obese, if you have a lot of belly fat, you are more likely to develop cancer.

Unlike the fat that sits just beneath the skin, the fat that sits around internal organs is called visceral fat.2 This fat is the most dangerous, and it is typically what shows up as belly fat. If you measure your waistline, you can get a good idea of whether you have a dangerous amount of belly fat. 

Women Men
Low health risk 31.5 inches or less 37 inches or less
Intermediate health risk 31.6 – 34.9 inches 37.1 – 39.9 inches
High health risk 35 inches or more 40 inches or more

Table 1. What does your waistline measurement mean? 2

Several studies have looked at the relationship between belly fat and cancer. One study followed over 150,000 post-menopausal women ages 50-79 for about 20 years.3 This study found that women who have extra belly fat are at higher risk of death regardless of their weight. Causes of death in the study included cardiovascular disease and cancer. The women of normal weight who had extra belly fat tended to be older, nonwhite, and with less education and income. They were also less likely to use menopausal hormones and to exercise. 

To figure out your BMI for the chart below, enter your height and weight into this calculator.

Apple Shape (Extra Belly Fat) Not “Apple Shape”
Not Overweight (BMI below 25) 20% more likely to die from cancer within 20 years
Overweight (BMI of 25-29.9) 19% more likely to die from cancer within 20 years 4% less likely to die from cancer within 20 years
Obese (BMI of 30 or higher) 26% more likely to die from cancer within 20 years 4% less likely to die from cancer within 20 years

Table 2. Likelihood of death due to cancer in women based on BMI.3

Women who were not overweight or obese but had extra belly fat were just as likely to die from cancer as overweight women with extra belly fat.

A different study followed over 3,000 men and women for 7 years.4 They used CT scans and physical exams to look at the fat throughout the body. Over the course of the study, the men and women developed 141 cases of cancer, 90 heart-related incidents, and 71 deaths from various causes. The study found that people with more belly fat, specifically visceral fat, were about 44% more likely to develop cancer and heart disease, even when adjusting for waist circumference. 

What can you do?

As you can see, belly fat can be very dangerous, especially for women, even if they are not overweight. Losing weight or preventing weight gain can lower health risks. By exercising regularly, you can get rid of unhealthy belly fat. It is also important to change your diet to eat foods that are high in nutrients and essential vitamins. You can do this by eating more fresh vegetables, nuts, and whole-grain breads instead of processed meat, red meat, candy, pasta, and white bread. These few changes can help you lose belly fat and improve the quality and length of your life.

Local bans on unhealthy food and drinks may also be effective in reducing belly fat. A 2019 study shows that a ban on the sale of sugar-sweetened beverages at a large college campus substantially decreased consumption and led to significantly less belly fat.5 Students who stopped drinking the beverages had improved insulin resistance and lower cholesterol. The combination of the ban and a brief motivational talk was even more effective than the ban by itself.

Learn more about how extra body fat can increase your risk for developing cancer, and how you can make a commitment to your health and reduce risky belly fat:


All articles on our website have been approved by Dr. Diana Zuckerman and other senior staff.



  1. Center for Disease Control and Prevention. FastStats- Overweight Prevalence. CDC.gov. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm. Updated June 13, 2016.
  2. Harvard Health Publishing. Abdominal obesity and your health. Health.Harvard.edu. https://www.health.harvard.edu/staying-healthy/abdominal-obesity-and-your-health. September 2005. Updated January 20, 2017.
  3. Sun Y, Liu B, Snetselaar LG, Wallace RB, Caan BJ, Rohan TE, et al. Association of Normal-Weight Central Obesity With All-Cause and Cause-Specific Mortality Among Postmenopausal Women. JAMA Network Open. 2019;2(7):e197337. https://www.ncbi.nlm.nih.gov/pubmed/31339542.
  4. Britton KA, Massaro JM, Murabito JM, Kreger BE, Hoffmann U, Fox CS. Body Fat Distribution, Incident Cardiovascular Disease, Cancer, and All-Cause Mortality. Journal of the American College of Cardiology. 2013; 62(10): 921-925. http://www.onlinejacc.org/content/62/10/921.
  5. Epel ES, Hartman A, Jacobs LM, Leung C, Cohn MA, Jensen L, et al. Association of a Workplace Sales Ban on Sugar-Sweetened Beverages With Employee Consumption of Sugar-Sweetened Beverages and Health. JAMA Network Open. 2019. doi:https://doi.org/10.1001/jamainternmed.2019.4434

Weight and cancer: What you need to know

Brandel France de Bravo, MPH, Noy Birger, and Sandy Wang, Cancer Prevention and Treatment Fund

There are many reasons why being overweight is bad for our health, but most people don’t realize that cancer is one of them.  Of course, excess body weight can contribute to serious medical conditions such as heart disease and type II diabetes, but new research shows that the habits that lead to excess body fat might also increase the risk of developing certain types of cancer.

In 2018, a study by American Cancer Society researchers published in the prestigious medical journal JAMA Oncology concluded that each year from 2011 to 2015, approximately 37,700 cancer cases in men in the U.S. (4.7% of all cancer cases excluding nonmelanoma skin cancers) and 74,700 cancer cases in women (9.6%) ages 30 years or older were attributable to excess body weight.[1]   Among men, the excess cancers ranged from 3.9% in Montana to 6.0% in Texas. In women, excess risk of cancer was almost twice as high as for men, ranging from 7.1% (in Hawaii to 11.4% in Washington, DC. The largest weight-related cancers were found mostly in southern and midwestern states, as well as Alaska and Washington, D.C.  Overall, the proportion of cancers attributable to excess body weight accounts for at least 1 in 17 of all cancers in each state.

Dr. Andrew Renehan and his colleagues estimated that more than 481,000 of newly diagnosed cancer cases worldwide in 2012 were due to overweight or obesity.[2] They estimated that North America had 111,000 cancer cases that were caused by being overweight or obese; this was calculated to be 23% of total global cancer cases (the highest of any region). Three cancers accounted for 73% of all obesity-related cancers among women globally: endometrial cancer, postmenopausal breast cancer, and colon cancer. For men, two cancers accounted for 66% of all obesity-related cancers: kidney and colon cancer. Other cancers that have been associated with overweight and obesity include prostate cancer, several gastrointestinal cancers, and non-Hodgkin’s lymphoma.

The good news is that a large 2014 study showed that with a healthy diet and regular exercise, post-menopausal women were able to significantly reduce their cancer risk.[3]  The researchers defined a healthy diet as one that limits red meat and processed meat, emphasizes whole grains over refined grains, and includes 2 and a half cups of vegetables and fruits every day; regular exercise meant at least 150 minutes of moderate intensity physical activity or 75 minutes of vigorous intensity physical activity every week. Those with the healthiest diets and most active lifestyles, saw their risk of breast cancer drop by 22%, their risk of colon cancer drop by 52%, and their overall risk of dying during the 12 years of the study drop by 27%!  While all the women who ate better and exercised more lowered their chances of developing cancer; non-white women seemed to benefit the most. 

A 2020 study of more than 8,000 Black and White Americans, men and women, also found that exercise helps lower the likelihood of dying from cancer. The study found that people who were inactive (whether coach potatoes or sitting at a desk all day and not getting exercise) were more likely to die from cancer, while those who engaged in light to moderate physical activity were less likely to die from cancer.[4]

How does obesity increase the risk of developing cancer?

What does excess body weight have to do with cancer, and why is being overweight even riskier for women? Researchers think that the danger of excess weight is partly due to the hormones secreted by fat tissues. One of those hormones is estrogen, which is known to increase the risk of breast cancer and endometrial cancer (also called cancer of the uterus) in women.[5,6] Fat cells also trigger a type of chronic immune response in the body because it recognizes that the extra fat is not supposed to be there, and so the immune system responds, causing inflammation in the body.[7] Long-term inflammation can prevent the immune system from working properly, making the body less able to fight off disease. In addition, chronic inflammation may cause insulin resistance,[8] which along with high blood sugar levels,[9] has been proposed as another explanation for why obesity increases the risk of cancer. The higher the insulin level of a breast cancer patient,[10] the greater the chance of death: insulin is believed to play a role in promoting tumor growth and in inhibiting cancer treatment.[11]

Having fat in certain places can also increase the risk for cancer. One study followed 3,086 men and women for up to seven years and used CT scans and physical exams to assess the fat deposits that accumulated in the abdomen region, liver, and tissues around the heart. Over the next seven years, the men and women in the study had 90 heart-related incidents, 141 cases of cancer, and 71 deaths (from various causes). After statistically controlling for the effect of age, exercise habits, BMI and self-reported eating habits, the researchers concluded that those with more abdominal fat were more likely to develop heart disease and cancer.[12]

It is not clear at what stage in life excess weight is most likely to increase the risk of cancer, pointed out by Dr. Marian L. Neuhouser, a nutritional epidemiologist at the Fred Hutchison Cancer Research Center in Seattle, and colleagues in a June 2015 study of obesity and breast cancer in 67,000 postmenopausal women. For example, during adolescence and pregnancy, breast cells undergo rapid division and differentiation. It is possible that excessive weight during those periods of this cell growth may be especially likely to increase the risk of breast cancer. Another susceptible time point may be the menopause, when breast tissue is also undergoing changes.[13]

How new is this news?

Researchers have been documenting the link between obesity and cancer for many years. More than a decade ago, the National Cancer Institute estimated that 20 to 30% of the most common cancers in the United States “may be related to being overweight and/or lack of physical activity” and might also “increase the risk of death from many cancers, accounting for up to 14% of cancer deaths in men and 20% of cancer deaths in women.”[14]  Every additional study fills in another piece of the puzzle, helping to explain which cancers “feed” off fat, and how it is that fat fuels tumor growth. Renehan et al’s 2012 study, which seemed to be groundbreaking at the time, is based in part on an earlier meta-analysis (a type of statistical analysis that combines many studies) in which many of the same authors analyzed more than 200 comparable data sets gathered from different countries around the world.[15]

The meta-analysis found that excess weight in men was most strongly associated with cancer of the esophagus (esophageal adenocarcinoma), the thyroid, colon cancer, and renal cancer (cancer of the kidneys). Being overweight did not appear to increase a man’s risk of prostate cancer (although a study in the U.S. has found that an overweight man with prostate cancer is more likely to die of it than a man with prostate cancer who is not overweight).[16] According to the meta-analysis, excess weight in women is most strongly associated with endometrial cancer, cancer of the gallbladder and the esophagus, and kidney cancer. A few other cancers were also associated with being overweight for both men and women, such as leukemia, multiple myeloma, and non-Hodgkin’s lymphoma, but the link was weaker. In men, rectal cancer and malignant melanoma also seemed to be related to weight, and women with higher BMI were slightly more likely to be diagnosed with post-menopausal breast cancer, cancers of the pancreas and thyroid, and colon cancer.

Renehans’s conclusions are quite consistent with the findings of other studies not included in the meta analysis.[17] For example, the American Institute for Cancer Research (AICR) estimated that excess body fat is responsible for 49% of endometrial cancers; 35% of esophageal cancers; 28% of pancreatic cancers; 24% of kidney cancers; 21% of gallbladder cancers; 17% of breast cancers; and 9% of colon cancers.[18] AICR estimates that will result in over 100,000 new cases of cancer each year due to excess body fat in the U.S.,[19] which is similar to the estimates of the 2018 American Cancer Society study.

Renehan did not find any significant link between obesity and ovarian cancer, but a more recent U.S. study did.[20] Neuhouser’s study, conducted at 40 U.S. clinical centers, of women ages 50 to 79 followed for about 13 years, showed that women who gained more than 5% of their baseline weight during the study’s follow-up period had a modest increased risk of breast cancer. The risk was greatest for women with a body mass index over 35 — they were 60% more likely to develop breast cancer than women of normal weight.

A 2016 study found that the link between obesity and cancer is stronger in some countries than others. Of the seven countries they studied, they found a pattern of increasing BMI in the countries of the Middle East compared to Asian countries. The high average BMI in the Middle East is associated with higher percentages of people with cancer. Likewise, North America and Europe has a large proportion of obesity-related cancers, while countries in sub-Saharan Africa and Asia had a smaller proportion of obesity-related cancer.[21]

Does losing weight reduce your risk of cancer?

Obesity is caused by too many calories in proportion to physical activity but where you get your calories (the kinds of foods you eat) and where you store your fat may also affect your cancer risk.  Several studies show that high dietary fat intake increases the risk of post-menopausal breast cancer,[22] prostate cancer,[23] and pancreatic cancer.[24]

Other studies have indicated that high fat diets increase the risk of death from cancer and that low fat diets reduce the chances of cancer recurrence.[25]  A diet high in fat is, of course, also likely to cause obesity, so it is very difficult to determine whether weight or diet is a stronger predictor of increased cancer risk. In other words, is it the fat you eat or the fat on your body that puts you at the greatest risk of cancer? And not all body fat is equal: abdominal fat, for instance, is associated with colon cancer.[26] Can losing weight prevent you from getting cancer? The evidence is clear for some cancers but not for others. Losing weight may reduce the risk of prostate cancer and definitely reduces the risk of reflux, an important risk factor for esophageal cancer.[27]

A 2009 study showed there were fewer cancer diagnoses in a group of formerly obese patients who had undergone bariatric surgery to reduce the size of their stomachs and lose weight compared to obese patients who hadn’t had this surgery.[28]

Several studies have found that intentional weight loss can reduce the risk of breast cancer, particularly when the weight loss is after menopause.[29,30,31] However, Neuhouser’s study found that already overweight or obese women who lost weight during the study did not lower their risk of breast cancer.[13]

Studies since Rehehan indicate that cancer risk drops after bariatric surgery—provided patients keep the weight off [32]—because of reduced hormone levels and inflammation, which are linked to cancer. [33,34]

What we know and don’t know

 All of these studies provide preliminary evidence that the cancer risk from being overweight or obese may be reversible and may not only be related to the types of food eaten or exercise habits, but also to the excess fat tissue.  In some of these studies, however, the people participating changed several habits at once, such as diet and exercise, so it is not always possible to determine if the reduction in cancer risk was related primarily to the physical weight loss, or to the change in diet or exercise, or both.

Excess body weight doesn’t only increase the risk of developing cancer and cause tumors to grow more quickly,[35,36] it can also make detecting and treating cancer more difficult.  If a person is very overweight, mammograms may be less accurate, tumors can be hard to feel, and veins for intravenous medication are not as easy to find. More importantly, doctors have difficulty determining the correct dose of medicine, and as a result, obese patients may not receive sufficient chemotherapy. Given these complications and the likelihood of other chronic health problems such as type 2 diabetes and heart disease, it is not surprising that cancer death rates are usually higher for people who are very overweight.

Overall, the research indicates that when weight goes up, so does the risk of many cancers. Similarly, when weight goes down, or is at least maintained throughout adulthood,[25] the risk of certain cancers also goes down.  These are studies of large numbers of people–looking at patterns and associations — so the findings do not mean that every obese person will get cancer or that slender people are protected from it. The exact relationship between cancer and excess body weight has not been clearly established. We still do not understand how an individual person’s diet, level of physical activity, and genes can all be factored together to calculate his or her cancer risk. What we do know is that there are many health benefits to achieving and maintaining a healthy body weight, including lowering the risk of cancer and improving cancer treatment outcomes.

Bottom Line

After giving up tobacco, watching your weight and staying active are your best forms of health insurance. For guidelines and tips on living a healthy lifestyle, read  Eating Habits to Improve Health and Lower Body Mass Index.

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

The National Center for Health Research is a nonprofit, nonpartisan research, education and advocacy organization that analyzes and explains the latest medical research and speaks out on policies and programs. We do not accept funding from pharmaceutical companies or medical device manufacturers. Find out how you can support us here.



  1. Islami F, Goding Sauer A, Gapstur SM, et al. Proportion of cancer cases attributable to excess body weight by US state, 2011-2015. JAMA Oncology, 2019; 5(3):384–392.  https://jamanetwork.com/journals/jamaoncology/article-abstract/2718923
  2. Arnold M, Pandeya N, Byrnes G, et al. Global burden of cancer attributable to high body-mass index in 2012: A population-based study. The Lancet Oncology. 2015; 16(1), 36–46. http://doi.org/10.1016/S1470-2045(14)71123-4
  3. Thomson CA, McCullough ML, Wertheim BC, et al. Nutrition and physical activity cancer prevention guidelines, cancer risk, and mortality in the Women’s Health Initiative. Cancer Prevention Research. 2014; 7 (1):42-53.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090781/
  4. Gilchrist SC, Howard VJ, Akinyemiju T, Judd SE, Cushman M, Hooker SP, Diaz KM. Association of Sedentary Behavior With Cancer Mortality in Middle-aged and Older US Adults. JAMA Oncology. 2020;6(8):1210–1217.
  5. Cleary MP, Grossmann ME. Obesity and breast cancer: The estrogen connection. Endocrinology. 2009; 150(6): 2537-2542.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689796/
  6. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: A synthetic review. Cancer Epidemiology, Biomarkers & Prevention. 2002; 11: 1531.  http://cebp.aacrjournals.org/content/11/12/1531.long
  7. Festa A, D’Agostino R Jr, Williams K, et al. The relation of body fat mass and distribution to markers of chronic inflammation. International Journal Obesity and Related Metabolic Disorders. 2001; 25:1407-1415. https://www.ncbi.nlm.nih.gov/pubmed/11673759
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  10. Hede K. Doctors seek to prevent breast cancer recurrence by lowering insulin levels. Journal of the National Cancer Institute. 2008; 100(8): 530-532.  https://www.ncbi.nlm.nih.gov/pubmed/18398091
  11. Boyd DB. Insulin and cancer. Integrative Cancer Therapies.  2003; 2(4): 315-329.   https://www.ncbi.nlm.nih.gov/pubmed/14713323
  12. Britton KA, Massaro JM, Murabito JM, et al.  Body fat distribution, incident cardiovascular disease, cancer, and all-cause mortality. Journal of the American College of Cardiology. 2013. 62(10), 921-925.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142485/
  13. Neuhouser ML, Aragaki AK, Prentice RL, et al. Overweight, obesity, and postmenopausal invasive breast cancer risk: A secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Oncology. 2015;1(5):611-621.  https://jamanetwork.com/journals/jamaoncology/fullarticle/2319235
  14. Cancer Trends Progress Report. National Cancer Institute, NIH, DHHS, Bethesda, MD, March 2020, https://progressreport.cancer.gov.
  15. Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies. The Lancet. 2008; 37(371(9612):569-578.   https://www.ncbi.nlm.nih.gov/pubmed/18280327 
  16. Wright ME, Chang SC, Schatzkin A, et al.  Prospective study of adiposity and weight change in relation to prostate cancer incidence and mortality. Cancer. 2007; 109(4):675-684.  https://www.ncbi.nlm.nih.gov/pubmed/17211863
  17. Lowrance WT, Thompson RH, Yee DS, et al. Obesity is associated with a higher risk of clear-cell renal cell carcinoma than with other histologies. BJU International. 2009; 105(1): 16-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818114/
  18. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US Adults, 1999-2008. JAMA. 2010; 303(3):  235-241.   https://jamanetwork.com/journals/jama/fullarticle/185235
  19. American Institute for Cancer Research. Large study finds (again) obesity links to many cancers. https://www.aicr.org/resources/blog/large-study-finds-again-obesity-links-to-many-cancers/. March 2017. 
  20. Leitzmann MF, Koebnick C, Danforth KN, et al. Body mass index and risk of ovarian cancer. Cancer. 2009; 115(4): 812-822.  https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19127552/
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  23. Giovannucci E, Rimm EB, Colditz GA et al. A prospective study of dietary fat and risk of prostate cancer. Journal of the National Cancer Institute. 1993; 85(19): 1571-1579.  https://www.ncbi.nlm.nih.gov/pubmed/8105097
  24. Thiébaut AC,   Jiao L, Silverman DT, et al. Dietary fatty acids and pancreatic cancer in the NIH-AARP diet and health study. Journal of the National Cancer Institute. 2009; 101(14):1001-1011.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724851/
  25. Chlebowski R. Lifestyle change including dietary fat reduction and breast cancer outcome. The Journal of Nutrition.  2007; 137: 233S-235S.   https://www.ncbi.nlm.nih.gov/pubmed/17182832
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  27. Wolin KY, Colditz GA. Can weight loss prevent cancer? British Journal of Cancer. 2008; 99(7): 995-999.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567071/
  28. Sjöström L, Gummesson A, Sjöström CD, et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): A prospective, controlled intervention trial.  Lancet Oncology. 2009; 10: 653-662.   https://www.ncbi.nlm.nih.gov/pubmed/19556163
  29. Harvie M, Howell A, Vierkant RA, et al. Association of gain and loss of weight before and after menopause with risk of postmenopausal breast cancer in the Iowa women’s health study. Cancer Epidemiology, Biomarkers & Prevention. 2005; 14: 656.  http://cebp.aacrjournals.org/content/14/3/656.long
  30. Elliott AM, Aucott LS, Hannaford PC, Smith WC. Weight change in adult life and health outcomes. Obesity Research. 2005; 13: 1784-1792.  https://www.ncbi.nlm.nih.gov/pubmed/16286526
  31. Parker ED, Folsom AR. Intentional weight loss and incidence of obesity-related cancers: The Iowa Women’s Health Study. International Journal of Obesity. 2003; 27: 1447-1452.  https://www.ncbi.nlm.nih.gov/pubmed/14634673
  32. Teras AL, Goodman M, Diver WR, et al. Weight loss and postmenopausal breast cancer in a prospective cohort of overweight and obese US women. Cancer Causes & Control. 2011; 22:573–579. https://www.ncbi.nlm.nih.gov/pubmed/21327461
  33. Byers T, Sedjo RL. Does intentional weight loss reduce cancer risk? Diabetes, Obesity and Metabolism. 2011; 13: 1063–1072.  https://www.ncbi.nlm.nih.gov/pubmed/21733057
  34. Harvie MN, Pegington M, Mattson MP, et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: A randomised trial in young overweight women. International Journal of Obesity (London). 2011; 35(5): 714–727.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017674/
  35. Brandon EL, Cantwell L, Gu JW, Hall, JE. Obesity enhances melanoma tumor growth independently of circulating leptin. The FASEB Journal. 2007; 21:763.3.   https://www.fasebj.org/doi/abs/10.1096/fasebj.21.6.A927-a
  36. Brandon EL, Gu JW, Cantwell L, et al. Obesity promotes melanoma tumor growth: Role of leptin. Cancer & Biology Therapy. 2009; 8(19):1871-1879.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796478/