Prevalence of Ischemic Heart Disease Risk Factors in Punjab and Application Statistical methods to predict Ischemic Heart Disease

risk

Contributors:

Ali Saleem Butt 5003-E, Ahmed Abdullah 596-E, Adil Suleman 5004E, Hashim Ali 587-E, Qasim Zia 591-E

Others

Muhammad Zeeshan 578-E, Muhammad Naseem 597-E, Hassam Tariq 594-E, Zuhaib Jaffer Malik 5011-E

University College of Pharmacy, University of the Punjab, Lahore

Risk Factor Prevalence & Risk Prediction Page 1

Abstract:
This study was conducted to assess cardiovascular Risk factor prevalence among different groups in our community and develop of risk assessment system through two different statistical methods. For this purpose, Ischemic heart disease patients suffering from coronary artery disease first time were observed. Data was collected from three different hospitals by survey of patients individually. After collection, the data was manipulated Using Frequency distribution charts and highly valuable information was obtained that is helpful in directing the community health services and program into the key directions for getting better outcome in reducing IHD. For advanced analysis and derivation of a risk prediction system, the data was fitted into Logistic regression model and Classification and Regression Model using SPSS 17 and R-Language. Logistic Regression model when applied to readily observed patients data, there was a good 81.3% correct prediction of disease development, though the factors themselves in the model are not statistically significant. Classification model was able to indicate a class with highest IHD risk which had Diseased to Healthy ratio of 2.285. This study can serve as a foundation for further research and paves a way for a more comprehensive study in this respect in future.

Risk Factor Prevalence & Risk Prediction Page 2

Introduction:
Coronary heart disease, also called coronary artery disease or ischemic heart disease, disease characterized by an inadequate supply of oxygen-rich blood to the heart muscle (myocardium) because of narrowing or blocking of a coronary artery by fatty plaques (see atherosclerosis). If the oxygen depletion is extreme, the effect may be a myocardial infarction (heart attack); if the deprivation is insufficient to cause infarction (death of a section of heart muscle), the effect may be angina pectoris, or spasms of pain in the chest.[1] Coronary Heart disease is the leading cause of deaths in all over the world. 80% of the deaths due to CVD and 86% of the global burden of CVD are in the developing countries. Despite the high death rates due to noncommunicable diseases, by 2010 the leading cause of death in the developing countries including Pakistan would be CVD [2]. For planning preventive and treatment strategies, the prevalence of the disease and its risk factors must be known. This study was therefore carried out to determine the prevalence of ischemic heart disease in Pakistan as well as that of its risk factors, so as the appropriate steps may be taken in order to decrease the occurrence of the disease in our community in future. Therefore, study was carried out to determine the risk factors involved in the development of ischemic heart disease in our local community (Punjab). Various risks Factors are involved in development of Ischemic Heart disease The following are confirmed independent risk factors for the development of CAD 1. Hypercholesterolemia (specifically, serum LDL concentrations 2. Smoking 3. Hypertension (high systolic pressure seems to be most significant in this regard) 4. Hyperglycemia (due to diabetes mellitus or otherwise) 5. Type A Behavioural Patterns, TABP. Added in 1981 as an independent risk factor after a majority of research into the field discovered that TABP's were twice as likely to exhibit CAD as any other personality type. 6. Hemostatic Factors:[3] High levels of fibrinogen and coagulation factor VII are associated with an increased risk of CAD. Factor VII levels are higher in individuals with a high intake of dietary fat. Decreased fibrinolytic activity has been reported in patients with coronary atherosclerosis. 7. Hereditary differences/genetic polymorphisms in such diverse aspects as lipoprotein structure and that of their associated receptors, enzymes of lipoprotein metabolism such as cholesteryl ester transfer protein (CETP) and hepatic lipase (HL),[4] homocysteine processing/metabolism, etc.

Risk Factor Prevalence & Risk Prediction Page 3 8. High levels of Lipoprotein(a),[5][6][7] a compound formed when LDL cholesterol combines with a substance known as Apoliprotein (a). 9. While detection of high levels of homocysteine has been linked to cardiovascular disease, lowering homocysteine levels may not improve outcomes.[8]

Significant, but indirect risk factors include:

Lack of exercise Consumption of alcohol Stress Diet rich in saturated fats\ Diet low in antioxidants Obesity Men over 60; Women over 65[9] A recent study done in India (Pondicherry) shows its association with hemoglobin [10]

There are various risk assessment systems for determining the risk of coronary artery disease, with various emphases on different variables above. A notable example is Framingham Score, used in the Framingham Heart Study. It is mainly based on age, gender, diabetes, total cholesterol, HDL cholesterol, tobacco smoking and systolic blood pressure.[11] But information about some of these factors is occasionally not available. So, for the sake of this study only the factors about which the data is frequently available in the society have been taken into account. These include direct as well as indirect factors like smoking, obesity, diabetes, anxiety, menopause, age, gender, body mass index, dietary fats, daily activity level, family history and hypertension.

Materials & Method

The research design used was a simple survey in which the patients fulfilling the patient selection criteria, from 3 major hospitals of Lahore, were approached and data was collected for analysis. The detailed information was collected about all the social and medical factors that contributed either directly or indirectly to development of Ischemic Heart Diseases. Then, the factors about which the information is generally and easily available in the community were isolated and based on this information a survey form was developed for data collection. Patient Selection Criteria and Total number of Cases Observed The criteria for the selection of a patient, was set. It includes the following points:

Risk Factor Prevalence & Risk Prediction Page 4 1) The patient has any type of Ischemic Heart Disease as its final diagnosis 2) The patient has showed first symptoms of the disease within last 5 years. Data from 47 randomly selected patients who from the following hospitals were collected: 1) Punjab Institute of Cardiology, Lahore 2) Jinnah Hospital, Lahore 3) Services Hospital, Lahore First, the data was sorted and simple frequency distribution results were compiled using statistical analysis techniques i.e. frequency distribution (among different categories) with the help of computer software SPSS 17 Statistics. Statistical Analysis: For more detailed insight of the data, advanced statistical techniques were used, including the determination of statistical significance of the individual risk factors using: Logistic Regression Model (using SPSS 17) Classification and Regression Tree (C&RT) method of data analysis (using R language) i) Binary logistic Regression Model: We took Ischemic Heart Disease (I.H.D) as a dependent variable with two Categories (No or Yes) along with a mixture of independent variables such as Age, Weight, Height, (weight and height were used to calculate Body Mass Index ), Gender, Smoking History, Diet Fat, Activity Level, Anxiety, Family History Diabetes Mellitus (DM), Hypertension (HTN) and Menopause. The age and BMI were taken as continuous variable while, Smoking History, Diet Fat, Activity Level, Anxiety, Family History Diabetes Mellitus (DM) and Hypertension (HTN) were taken as ordinal variable. Gender and Menopause were taken as nominal variables. Logistic regression model was applied using SPSS 17and the results were obtained and analyzed. ii) Classification and Regression Trees: The data was analyzed with Classification and Regression Tree (CART) using R-Language as a tool and a class with the highest number of patients with least number of factors involved was isolated. This class represents the persons with the most risk of IHD.

Risk Factor Prevalence & Risk Prediction Page 5

Results
Distribution of Risk Factors among different categories: The data was collected and results were compiled to assess the prevalence of IHD risk factors in the community. The following information was revealed: 1. The percentage distribution of risk factors (direct as well as indirect) among all the 47 IHD patients is as below:
Risk Factor/Category Male Female Age in 40s Age in 50s Smokers Diabetes Over Weight OBESE Dietary Fat Low Physical Activity Family History Hypertension Anxiety Edu. (Below matric) Edu. (matric intermediate) Edu. (Graduation & Above) %age of Patients 71.74 28.26 30.43 67.39 39.13 34.78 34.78 21.74 73.91 52.17 47.83 52.17 54.35 39.13 34.78 21.74

2. The percentage distribution of risk factors (direct & indirect) among males and females in the observed patients group is as follows:
Risk Factor Frequency (Gender wise) Age in 40s Age in 50s Smokers Diabetes Over Weight OBESE Dietary Fat Low Physical Activity Family History Hypertension Anxiety Post Menopausal Males (%age) 27.27 69.69 51.51 30.3 39.39 15.15 78.78 48.48 45.45 39.39 48.48 0 Females (%age) 38.46 61.53 7.69 46.15 23.07 38.46 61.53 61.53 53.84 84.61 69.23 69.23

Risk Factor Prevalence & Risk Prediction Page 6

3. Here are the percentage distribution of risk factors among different age groups as observed from the patient data:
Risk factors frequency (Age group wise) Male Female Smokers Diabetes Over Weight OBESE Dietary Fat Low Physical Activity Family History Hypertension Anxiety 40s (%age) 64.286 35.714 28.571 0 28.571 28.571 78.571 35.714 57.143 64.286 64.286 50s (%age) 78.5714 21.4286 28.5714 50 28.571 21.43 71.4286 50 35.71 50 64.2 60s & above (%age) 70.58 29.41 52.94 52.94 41.17 17.64 70.58 64.7 52.94 47.05 41.17

4. And these are the percentage distribution of risk factors among different education categories based on the data collected:
Risk factors frequency Male Female Age in 40s Age in 50s Smokers Diabetes Under Matric (%age) 66.67 33.33 38.88 55.55 38.88 11.11 Matric to Intermediate (%age) 75 25 25 75 50 56.25 Graduation or above (%age) 80 20 30 70 30 30

Risk Factor Prevalence & Risk Prediction Page 7

Over Weight OBESE Dietary Fat Low Physical Activity Family History Hypertension Anxiety 33.33 22.22 72.22 50 38.88 38.88 44.44 31.25 25 81.25 56.25 31.25 62.5 43.75 40 20 80 50 80 60 90

Advanced statistical analysis By applying Logistic Regression Model: When the Logistic Regression Model was fitted into the data comprising of 46 patients and 50 healthy individuals, the following results were obtained:
Omnibus Tests of Model Coefficients Chi-square Step 1 Step Block Model 22.369 22.369 22.369 df 11 11 11 Sig. .022 .022 .022

The table above shows that when the Omnibus Test was conducted on the applied logistic regression model, it proves to be reliable and appropriate as the significance value for the model is 0.022, which is less than 0.05. The table below enlists the coefficients and significances associated to the risk factors observed, as obtained by the applied model:

Risk Factor Prevalence & Risk Prediction Page 8

Variables in the Equation B Step 1a Age Gender(1) Smoking Diabetes BodyMassIndex DietFats ActivityLevel FamilyHistory Hypertension Anxiety MenoPause Constant .055 3.021 .848 1.533 .078 .374 -.313 .601 1.295 -.578 .491 -9.075 S.E. .038 12.514 1.047 1.025 .096 .574 .510 .819 .822 .821 1.469 13.195 Wald 2.095 .058 .656 2.239 .664 .425 .377 .538 2.482 .495 .112 .473 df 1 1 1 1 1 1 1 1 1 1 1 1 Sig. .148 .809 .418 .135 .415 .514 .539 .463 .115 .482 .738 .492 Exp(B) 1.057 20.510 2.336 4.634 1.081 1.454 .731 1.824 3.652 .561 1.633 .000

a. Variable(s) entered on step 1: Age, Gender, Smoking, Diabetes, BodyMassIndex, DietFats, ActivityLevel, FamilyHistory, Hypertension, Anxiety, Menopause.

If significance value less than or equal to 0.05 is considered as significant, no risk factor is below our threshold significance value and thus no factor can be reliably related to the disease development. Yet based on the results, the most significant of all factors is Hypertension (significance value = 0.115). Diabetes has significance value of 0.135. Some of other relatively significant risk factors are Diabetes (significance value = 0.135) and Age (Significance value = 0.148). The possible reasons for insignificance of the results are: 1. There is relatively may be a weaker relationship between these variables and IHD pathogenesis. 2. As the significance of statistic not only depends on the strength of relationship between two variables but also on the number of observations made, in-sufficient data can be the other possible reason for such results.

Risk Factor Prevalence & Risk Prediction Page 9 Coefficients (B) of Logit equation: The coefficients (B) of Logit equation of the applied logistic regression model for the relatively more significant factors i.e. hypertension, diabetes and age, are all positive values. Coefficient of hypertension is 1.295 with Odds ratio (represented by Exp(B) in the table) of 3.652 means that in hypertensive persons there is 3.652 times higher risk of IHD. Similarly Diabetes and age have coefficient value of 1.533 and 0.055 respectively. The odds values of these factors show that the people with diabetes have 4.634 times more risk of IHD development and 1.057 times additional risk for each year of age. The Model With coefficient values given above, the logit equation can be written as: Logit = Z = - 9.075 + Age * 0.055 + Gender * 3.021 + Smoking * 0.848 + Diabetes * 1.533 + BMI * 0.078 + Dietary Fats * .374 + ActivityLevel * -.313 + FamilyHistory * .601 + Hypertension * 1.295 + Anxiety * -.578 + Menopause * 0.491 Risk Factor
Age Gender Smoking Diabetes BodyMassIndex DietFats ActivityLevel FamilyHistory Hypertension Anxiety MenoPause Low = 1 Low = 1 Present = 1 Present = 1 Present = 1 Present = 1 Moderate =2 Moderate =2 Absent = 0 Absent = 0 Absent = 0 Absent = 0 Male =0 Present = 1 Present = 1 Female = 1 Absent = 0 Absent = 0 BMI value High =3 High =3 Value Age in years

Z value is then put into the following function, P(IHD) = ez / (1+ez) that gives the probability of IHD in any particular case. Performance of the model: When the model is applied to the recorded cases, the following case distribution chart is obtained.

Risk Factor Prevalence & Risk Prediction Page 10

According to the model and as depicted in the chart above, there is a mild degree of miss classification (18.7% of the observed cases) when it is applied to the data. So, the model can predict the disease probability in the people but not very reliably. The reasons for the insignificance of results can be: 1. Inadequate data (too small sample size) 2. Biasing during data collection (Not random fully representative sample) 3. Some other statistical model could have been used e.g. Simultaneous Equation Model

Risk Factor Prevalence & Risk Prediction Page 11 Classification and Regression Tree: (CART) Using R language as the tool, the data was analyzed and the following classification tree was obtained.

Risk Factor Prevalence & Risk Prediction Page 12

Explanation:

Risk Factor Prevalence & Risk Prediction Page 13 Among total 56 persons were observed. 46 persons were diseased and 10 patients were healthy. At each level, there is a condition (decision). The right branch represents the negative class i.e. the condition is not met for the cases in that class, and the left branch represents positive class i.e. for which the condition is met. At first level, the data is split into two classes based on the condition: Age is smaller than 30.5 years (Age > 30.5 years) Positive class on the left has 3 (30% of the total healthy individuals) healthy persons and 0 (0% of the total diseased persons) diseased persons. The negative class on the right has 7 healthy persons (70% of the total healthy persons) and 46 diseased persons (100% of the total diseased persons). At second level, the right class (negative class) with respect to diseased persons is split into further classes based on the condition: Activity Level is larger than or equal to 1.5 (Activity Level >= 1.5) Or Activity level = Moderate or High Positive class on the left has 6 (60% of the total healthy individuals) healthy persons and 22 (47.8% of the total diseased persons) diseased persons. The negative class on the right has 1 healthy person (10% of the total healthy persons) and 24 diseased persons (52.2% of the total diseased persons). At third level, the left hand class (Positive class) is further sub classified based on the condition: Age is more than or equal to 68.5 years (Age >68.5 years) Positive class on the left has 2 healthy persons (20% of the total healthy individuals) and 0 diseased persons (0 % of the total diseased persons). The negative class on the right has 4 healthy person (40% of the total healthy persons) and 22 diseased persons (47.8% of the total diseased persons). At fourth level, the right hand class having 40% healthy and 47.8% diseased persons is further split in order to get maximum separation between the diseased and the healthy persons, using the following criteria: Hypertension duration above or equal to 7.5 years (Hypertension duration >= 7.5 years)

Risk Factor Prevalence & Risk Prediction Page 14 Positive class on the left has 2 (20% of the total healthy individuals) healthy persons and 1 (2.2% of the total diseased persons) diseased persons. The negative class on the right has 2 healthy person (20% of the total healthy persons) and 21 diseased persons (45.7% of the total diseased persons). Classification tree shows, only three factors are significant, namely Age, Hypertension duration and Activity Level.

Risk Factor Prevalence & Risk Prediction Page 15

Discussion
By analyzing the distribution of risk factors we conclude the following important points: The most prevalent risk factor overall for IHD in the community is High Dietary Fat Intake as it is present in 74 percent of the IHD patients. So, generally, in order to improve community health, efforts must be made to lower the prevalence of high fat intake in the individuals. Public awareness campaigns have to be directed primarily in this direction to reduce the probability of IHD in the community significantly. The second highest occurrence belongs to Anxiety that is there in 54.35 percent of the patients. It is the secondary concern, especially in the perspective of current social atmosphere in the society where prevalence of anxiety, mostly generalized anxiety disorder has tremendously increased. And the fact that it is the most neglected disorder that is rarely diagnosed, given importance and treated as a disease, makes the circumstances even more critical. Although the anxiety was not proved to be significant factor in this study, it can be a significant contributor to the IHD cases in the community as a whole due to its high prevalence and already proved significance as IHD risk factor. The other factors i.e. Hypertension (52.17%), Low Physical Activity (52.17%) and Family History (47.83%) are also present in comparatively higher frequency and can be important reasons for increasing number of IHD cases day by day. Male vs Female Patients: This comparison shows some very interesting facts about the risk factors distribution among genders. 1. Hypertension is the most prevalent risk factor among female patients (84.61%) while in males, it contributes in merely 39.39 % of IHD patients. 2. Anxiety and Obesity are also more prevalent in females (69.23% and 38.46% respectively) than in males (48.48 % and 15.15% respectively of the total male cases). 3. Female patients that are diabetic as well are 46.15% while those of men are 30.3%, showing high precedence of diabetes in females than in males leading to IHD. 4. The high number of postmenopausal women (69.23% of total Female patients) is also indicative to the proposed fact that menopause poses an additional risk of IHD to females. 5. The only significant factor present in high frequency in males compared to females is smoking. (51.51% males and 7.69% females)

Risk Factor Prevalence & Risk Prediction Page 16 Patients among Different Age groups: Most of the risk factors are equally distributed among the three different age group categories (i.e. patients in 40s, patients in 50s and patients in 60s or above). Some of the important outcomes are as follows: 1. The frequency of low physical activity increases with the increasing age group. So, with advancing age, there is usually low physical activity that can add to the risk of IHD. 2. Hypertension and anxiety are more prevalent in younger age groups i.e. 40s and 50s groups. It signals that there can be a correlation among these two factors. Moreover, the high frequency of anxiety among 40s patients (64.29%) compared to the 60s or above patient group (41.17%) indicates the high stress life styles specially in younger persons who are more often indulged in working and earning issues than the seniors in our community. 3. A positive smoking history is more prevalent among the senior age group patients, in 60s and above (52.94%) compared to the 28.57% in patients in 40s and 28.57 % in those in 50s. It can be interpreted as the hypothetical statement that smoking has a slow but continuously mounting with time effect on IHD development that results in IHD in later in age. Patient Risk Factor Prevalence (Education wise): The percentage frequency chart of risk factors among different education categories shows these significant results. 1. Anxiety is present in 90% of the patients with graduation or above education, compared to the 44.44% and 43.75% in undermatric and from matric to intermediate groups respectively. It shows that anxiety being more common in highly educated individual that can be attributed to their more mental stressing nature of job, can be major contributing factor in this group. It also indicates a need to counsel that group to change their life styles with a target to lessen the anxiety and thus, IHD risk. 2. Family history is also more common among the graduation or above group being present in 80% of the patients while for undermatric and matric to intermediate groups the percentages are 38.88% and 31.25% respectively. One possible reason to such a conclusion is more awareness of the educated group about the IHD and thus, their better ability to identify and indicate a positive family history during data survey than those with less education. Advanced Statistical Analysis: Binary Logistic Regression Model: When Binary Logistic Regression Model was fitted into the data the results shows that no factor comes out to be significant. The factors with relatively more significance compared to the other are Hypertension (significance value = 0.115), Diabetes (significance value = 0.135) and Age (significance value = 0.148).

Risk Factor Prevalence & Risk Prediction Page 17 The other factors like smoking, gender, body mass index, dietary fats, daily activity level, family history, menopause and anxiety level have proven to be strongly associated with IHD development in a number of research papers, but they come out to be very less significant in the model applied here. There is no factor that is significant enough statistically. The reasons can be: 1. There is relatively weaker relationship between these variables and IHD pathogenesis compared to the other variables (i.e. Age, hypertension, gender and menopause) that come out to be significant 2. As the significance of statistic not only depends on the strength of relationship between two variables but also on the number of observations made, in-sufficient data can be the other possible reason for such results. 3. The data obtained may not be an ideal representative random sample of the population and may have been influenced by biasing, especially during incorporation of data of healthy persons. The distribution chart of observed groups and their predicted disease probabilities shows a mild degree of miss classification (18.7%) which shows that despite of insignificance of the results, the logistic regression equation derived by fitting the model is able to predict the disease with moderate precision. Classification and Regression Model: By applying this model, only three factors come out as significant i.e. Age, Hypertension duration and Activity Level. It also shows that the class at highest risk of IHD is the one with: 1: age above 30.5 years and less than or equal to 68.5 years 2: activity level moderate or high 3: hypertension for more than or equal to 7.5 years Because here the percentage of healthy persons is 20% while that of diseased is 45.7%. The ratio of diseased to healthy persons for this class is 2.285 showing significant high risk in this class for IHD.

Conclusion:
The frequency distribution of IHD risk factors among different categories shows many important findings about the risk factors prevalence in the community. It directs us to the areas among specific groups in the community requiring special workout in order to control the IHD prevalence. Having targets pointed out, better results can be obtained from community health awareness programs to decrease IHD cases in the days to come. Although the advanced statistical analysis has not produced very appreciable results, this study can serve as a foundation for further research and paves a way for a more comprehensive study in this respect.

Risk Factor Prevalence & Risk Prediction Page 18

Bibliography:
1. Encyclopedia Britannica 2011, Coronary artery disease, Encyclopedia Britanica.inc. ISBN 159339-292-3 2. WHO,Global Health Observatory Data Repository,2008 3. Smith FB, Lee AJ, Fowkes FG, Price JF, Rumley A, Lowe GD (November 1997). "Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study". Arterioscler Thromb Vasc Biol. 17 (11): 33215. doi:10.1161/01.ATV.17.11.3321. PMID 9409328. 4. Ghatrehsamani K, Darabi M, Rahbani M, Hashemzadeh Chaleshtory M, Farrokhi E, Noori M (2009). "Combined hepatic lipase -514C/T and cholesteryl ester transfer protein I405V polymorphisms are associated with the risk of coronary artery disease". Genet Test Mol Biomarkers 13 (6): 80915. doi:10.1089/gtmb.2009.0080. PMID 19810818. 5. Danesh J, Collins R, Peto R (2000). "Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies". Circulation 102 (10): 10825. doi:10.1161/01.CIR.102.10.1082. PMID 10973834. 6. Smolders B, Lemmens R, Thijs V (2007). "Lipoprotein (a) and stroke: a meta-analysis of observational studies". Stroke 38 (6): 195966. doi:10.1161/STROKEAHA.106.480657. PMID 17478739. 7. Schreiner PJ, Morrisett JD, Sharrett AR, Patsch W, Tyroler HA, Wu K, Heiss G (1993). "Lipoprotein(a) as a risk factor for preclinical atherosclerosis". Arterioscler. Thromb. 13 (6): 82633. doi:10.1161/01.ATV.13.6.826. PMID 8499402. 8. "Women and heart disease | Health News | Find Articles at BNET".[dead link] 9 . Padmanaban P, Toora BD. Hemoglobin: Emerging marker in stable coronary artery disease. Chron Young Sci [serial online] 2011 [cited 2011 Jul 24];2:109-10. Available from: http://www.cysonline.org/text.asp?2011/2/2/109/82971 framinghamheartstudy.org > Coronary Heart Disease (10-year risk) (based on Wilson, D'Agostino, Levy et al. 'Prediction of Coronary Heart Disease using Risk Factor Categories', Circulation 1998 11. Mart-Carvajal AJ, Sol I, Lathyris D, Salanti G (2009). Mart-Carvajal, Arturo J. ed. "Homocysteine lowering interventions for preventing cardiovascular events". Cochrane Database Syst Rev (4): CD006612. doi:10.1002/14651858.CD006612.pub2. PMID 19821378. 12. Haldane J (1895). "The action of carbonic oxide on man". J Physiol 18 (56): 430462. 13. "Health : Young smokers' heart attack risk". BBC. 2004-08-24. Retrieved 2005-12-18. 14. "Cigarette Smoke Changes Heart's Shape". InfoNIAC.com. Retrieved 2009-01-10. 15 Grundy SM, Brewer HB, Cleeman JI, et al. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109: 4338. 16. Snyder EE, Walts B, Perusse L, et al. The human obesity gene map: the 2003 update. Obes Res 2004; 12: 369439 17.Olshansky SJ, Passaro DJ, Hershow RC, et al.A potential decline in life expectancy in the United States in the 21st century.N Engl J Med2005; 352: 113845. 18.Betsy B. Dokken, PhD, NP, CDE,The Pathophysiology of Cardiovascular Disease and Diabetes: Beyond Blood Pressure and Lipids,American diabetes association.

Risk Factor Prevalence & Risk Prediction Page 19

19.Smith, Timothy W.; Ruiz, John M. Journal of Consulting and Clinical Psychology, Vol 70(3), Jun 2002, 548-568.) 20. Mendelsohn ME, Karas RH, 1999 The protective effects of estrogen on the cardiovascular system. N Engl J Med 340: 1801-1811. 21. Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, Wise PM, 2006 Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies. Endocr Rev 27: 575-605. 22. Mendelsohn ME, 2002 Genomic and nongenomic effects of estrogen in the vasculature. Am J Cardiol 90: 3F-6F. 23. Venkov CD, Rankin AB, Vaughan DE, 1996 Identification of authentic estrogen receptor in cultured endothelial cells. A potential mechanism for steroid hormone regulation of endothelial function. Circulation 94: 727-733. 24. Losordo DW, Kearney M, Kim EA, Jekanowski J, Isner JM, 1994 Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of pre-menopausal women. Circulation 89: 1501-1510. 25. Liu PY, Christian RC, Ruan M, Miller VM, Fitzpatrick LA, 2005 Correlating androgen and estrogen steroid receptor expression with coronary calcification and atherosclerosis in men without known coronary artery disease.JClinEndocrinolMetab 90: 1041-1046. 26. Witteman JC, Grobbee DE, Kok FJ, Hofman A, Valken-burg HA, 1989 Increased risk of atherosclerosis in women after the menopause. BMJ 298: 642-644. 27. WHO Tobbaco Recommendations: Waterpipe Tobacco Smoking: Health Effects, Research Needs and Recommended Actions by Regulators http://www.who.int/tobacco/global_interaction/tobreg/Waterpipe%20recommendation_Final.pdf 28. World Health Organization and International Diabetes Federation (1999). Definition, diagnosis and classification of diabetes mellitus and its complications. Geneva, Switzerland: World Health Organization. 29. "BMI Classification". World Health Organization. 30. American Journal of Epidemiology ,Volume149, Issue6 , Pp. 531-540 Dietary Fat and Coronary Heart Disease: A Comparison of Approaches for Adjusting for Total Energy Intake and Modeling Repeated Dietary Measurements 31. British Heart Foundation. http://www.bhf.org.uk 32. Breiman, Leo; Friedman, J. H., Olshen, R. A., & Stone, C. J. (1984). Classification and regression trees. Monterey, CA: Wadsworth & Brooks/Cole Advanced Books & Software. ISBN 978-0412048418