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Association & Causation
1
Dr. Ravi Prakash
JR-III
Dept. of Community Medicine
Katihar Medical College
1
Why is Association & Causation
important?
 To decide if a factor A causes disease B or not!
 Is the link true or only facile?
 Is it true or by chance?
 If we know the cause(s) we can cure/treat
/prevent/minimize the illness. (in a patient or the
society)
2
Association & Causation
Association
 Relation between two or more
variables
 Generally found in snapshot
(cross-sectional) studies
 Relationships can be positive or
negative
 Correlation! (factors moving
together– like poverty and under
nutrition)
Causation
 A variable (s) lead to another
variable that is dependent/
outcome/ event/disease
 So it suggests Etiology of
disease
 We need analytical studies to
find out/prove cause(s)
3
Associatio
n
Defined as occurrence of two variables more often than would be
expected by chance.
An association is present if probability of occurrence of a variable
depends upon one or more variable.
4
CAUSATION
Precipitating
Factors
Predisposing
Factors
Enabling
Factors
Reinforcing
Factors
Age, Sex, Previous Illness
Exposure to agent
Low SEC, malnutrition
Repeated Exposure
Factors involved
in Causation
5
CAUSE - an event, condition, characteristic (or a combination)
which plays an important role / regular / predicable change in
occurrence of the outcome (e.g. smoking and lung cancer)
TYPES OF ASSOCIATION
1. SPURIOUS ASSOCIATION
2. INDIRECT ASSOCIATION
3. DIRECT (Causal) ASSOCIATION
A. One-to-One Causal association
B. Multi-Factorial Causation 6
Pyramid Of Associations
Causal
Non-causal
Confounded
Spurious
Positive /negative
Raj Bhopal : Cause and effect: the epidemiological approach
7
 Positive:Occurrence of higher value of a predictor variable
is associated with occurrence of higher value of another
dependent variable.
 Negative: Occurrence of higher value of a predictor variable
is associated with lower value of another dependent variable.
Ex - Female literacy and IMR
8
 Causal: Independent variable mustcause change in dependent
variable.
Ex – salt intake and hypertension
 Non-causal: Non-directional association between two variables.
Ex – alcohol use and smoking
9
Spurious Association
Spurious (not true) association
•Not real, only apparent
Example1: A study in UK of 5174 births at home and 11156 births at
hospitals showed perinatal mortality rates of 5.4/1000 in home
birth and 27.8/1000 in hospital births. (but this is spurious)
Exapmle2: Fire and Fire Brigade may be found together in a
snapshot--but Fire brigade is not the cause of FIRE.
10
SPURIOUS ASSOCIATION
 Some observed associations b/n a suspected factor and disease
may not be real
This Fallacy of presumption arises when two variables are
improperly compared (due to Bias).
PMR
Home Deliveries (5174)
Perinatal
Mortality
Rate
Hosp Deliveries (11,156)
27.8 / 1000
5.4 / 1000
11
INDIRECT ASSOCIATION
 It is a statistical association between a characteristic of
interest and a disease due to the presence of another
factor i.e. common factor (confounding variable)
12
E- Goitre
Altitude
Iodine Deficiency
(Confounding Factor)
Yudkin & Roddy’s wrong hypothesis on Sucrose and CHD association
(Smoking is the Confounder).
Jacob Yerushalamy identified the association b/n Smoking and Low
birth weight babies is due to Confounding.
13
14
Confounding Factor
1.
15
DIRECT ASSOCIATION
A. One-to-One Causal Relationship
This model suggests that two factors (A & B) exhibit one
to one relationship, if – Change in A is followed by Change in B.
Cause (A) Effect (B)
16
DIRECT ASSOCIATION
A. One-to-One Causal Relationship
This model suggests that two factors (A & B) exhibit one
to one relationship, if – Change in A is followed by Change in B.
Cause (A) Effect (B)
Paramyxo Virus Measles
17
KOCH’S POSTULATES (Germ Theory of Disease)
Hemolytic Streptococci
1. Necessary, and
2. Sufficient.
But this model does not fit well for many diseases, like in
Tuberculosis, tubercle bacilli is clearly a necessary factor, but its
presence may or may not be sufficient to produce the d/s.
 A Single Factor may produce several Outcomes.
Erysipelas
Scarlett Fever
Tonsillitis
18
B. Multifactorial Causation
In Several Modern Diseases, more than one factor is
implicated in the Web of Causation.
Eg: Both Asbestos exposure and Smoking cause Lung
Cancer independently.
As our Knowledge on disease increases, we may discover a
common biochemical event, which can be altered by each of these
factors
19
 Multiple factor leads to the disease.
 Common in non-communicable diseases
 Alternative causal factors each acting independently.
Ex: In lung cancer more than one factor (e.g. air pollution, smoking,
heredity) can produce the disease independently.
Either the causes are acting
Independently OR Cumulatively
20
Smoking
Air pollution Reaction at cellular level Lung cancer
Air pollution Reaction at cellular level Lung cancer
+
Exposure to asbestos
Independently
Exposure to asbestos
Cumulatively
Smoking
+
21
CAUSATIO
N
22
General Models of Causation
 The most widely applied models are:
– The epidemiological triad (triangle),
– The web
– The wheel and
– The sufficient cause and component causes models
(Rothman’s component causes model)
23
Epidemiological triad
Agent Factors
Physical Agents
Chemical Agents
Biological Agents
Nutritional agents
Host Factors
Socio-demographic Factors
Psycho-social Factors
Intrinsic Characteristics
Environmental
Factors
Physical Environment
Biological Environment
Social Environment 24
Web of Causation
DISEAS
E
25
Web of Causation - CHD
CHD
26
Rothman’s Component Causes and
Causal Pies Model
• Rothman's model has emphasised that the causes of disease comprise
a collection of factors.
• These factors represent pieces of a pie, the whole pie (combinations of factors)
are the sufficient causes for a disease.
• It shows that a disease may have more than one sufficient cause, with each
sufficient cause being composed of several factors
27
• The factors represented by the pieces of the pie in this model are called
component causes.
• Each single component cause is rarely a sufficient cause by itself, But may
be necessary cause.
• Control of the disease could be achieved by removing one of the components in
each "pie" and if there were a factor common to all "pies“ (necessary cause) the
disease would be eliminated by removing that
alone.
A
U B
C
N 28
A
U B
C
N
Known components (causes) – A,
B,
C
Unknown component (cause) -
U
N – Necessary cause
Known components causes
+
Unknown component cause = Sufficient cause
+
Necessary cause 29
TYPES OF CAUSAL
RELATIONSHIPS
30
If a relationship is causal, four types of causal relationships are possible:
(1) Necessary And Sufficient
(2) Necessary, But Not Sufficient
(3) Sufficient, But Not Necessary
(4) Neither Sufficient Nor
Necessary
31
 A factor is both necessary and sufficient for producing the disease.
 Without that factor, the disease never develops and in the presence of
that factor, the disease always develops
Types of causal relationships I:
Each factor is both necessary and sufficient
FACTORA DISEASE
32
Necessary and Sufficient
Necessary, But Not Sufficient
 Each factor is necessary, but not, in itself, sufficient to cause the disease .
 Thus, multiple factors are required, often in a specific sequence.
 Ex: Carcinogenesis is considered to be a multistage process involving both initiation
and promotion. A promoter must act after an initiator has acted. Action of an initiator
or a promoter alone will not produce a cancer.
33
DISEASE
Factor A
+
Factor B
+
Factor C
34
CANCER
Initiator
+
Promoter
+
Trigger
35
Sufficient But Not Necessary
 The factor alone can produce the disease, but so can other factors that are
acting alone
 Either radiation or benzene exposure can each produce leukemia without
the presence of the other.
 Even in this situation, however, cancer does not develop in everyone who
has experienced radiation or benzene exposure, so although both factors
are not needed, other cofactors probably are. Thus, the criterion of sufficient
is rarely met by a single factor.
36
Radiation
Or
Benzene Exp
Or
Smoking
Leukemia
37
 A factor by itself, is neither sufficient nor necessary to produce disease
 This is a more complex model, which probably most accurately represents
the causal relationships that operate in most chronic diseases.
Types of causal relationships: IV.
Each factor is neither sufficient nor necessary
38
Neither Sufficient Nor Necessary
– Temporal association
– Strength of association
– Specificity of association
– Consistency of association
– Biological plausibility
– Coherence of association
39
Additional criteria for judging causality
Temporal association
 The causal attribute must precede the disease or unfavorable
outcome.
 Exposureto the factor must have occurred before the disease
developed.
 Length of interval between exposure and disease very important.
 Its more obvious in acute disease than in chronic disease.
40
Temporal relationship (Relationship with
time)
• Cause must precede the effect.
o Drinking contaminated water -occurrence of diarrhea.
o However in many chronic cases, because of insidious onset and ignorance of
precise induction period, it become hard to establish a temporal sequence as
which comes first -the suspected agent or disease.
41
Strength Of The
Association
 Relationship between cause and outcome could be strong or
weak.
 With increasing level of exposure to the risk factor an increase in
incidence of the disease is found.
• Strength of association can be estimated by relative risk.
• Relative risks/Odds ratio greater than 2 can be considered strong
• Larger the relative risk, greater the likelihood of a causal association.
42
Dose-Response
Relationship
( The Biological gradient )
 As the dose of exposure increases, the risk of disease also increases
 If a dose-response relationship is present, it is strong evidence for a causal
relationship.
 However, the absence of a dose-response relationship does not
necessarily rule out a causal relationship.
 In some cases in which a threshold may exist, no disease may develop up to a
certain level of exposure (a threshold); above this level, disease may develop
43
 The causal relationship of cigarette smoking and lung cancer
has been based on three points.
Relative risk
Dose-response relationship
Decrease in risk on cessation of smoking
44
Biologic Plausibility Of The
Association
 The association must be consistent with the other knowledge (viz
mechanism of action, evidence from animal experiments etc).
 Sometimes the lack of plausibility may simply be due to the lack of
sufficient knowledge about the pathogenesis of a disease, so the criterion of
biological plausibility should not be applied rigidly.
 It is difficult to demonstrate where the confounder itself exhibits a
biological gradient in relation to the outcome. 45
e.g. – cigarette smoking and lung cancer hypothesis is biologically
plausible.
Food intake and cancer are interrelated is an old one.
Positive association of intestine, rectum, and breast cancer is
biologically logical.
46
Consistency Of The
Association
 Consistency is the occurrence of the association at some other time
and place repeatedly.
 Repeated observation of an association in different populations
under different circumstances.
 Example: consistent association between lung cancer and cigarette
smoking – 50 retrospective study and almost 9 prospective studies.
47
Specificity Of The
Association
 Specific exposure is associated with only one disease.
 Specificity implies a one to one relationship between the cause and
effect.
 It’s the most difficult to occur for 2 reasons:
 Single cause or factor can give rise to more than 1 disease
 Most diseases are due to multiple factors.
 Ex: Smoking is associated with many diseases.
• Not everyone who smokes develops cancer
• Not every one who develop cancer has smoke 48
Coherence of the association
 Based on available evidence or should be coherence with known facts that
are thought to be relevant.
 i.e. historic evidence of rising consumption of tobacco in form of cigarette
and rising incidence of lung cancer are coherent.
49
Deriving causal inferences: example
Assessment of the Evidence Suggesting Helicobacter pylori Ulcers as
a Causative Agent of Duodenal
1. Temporal relationship.
• Helicobacter pylori is clearly linked to chronic gastritis. About 11% of
chronic gastritis patients will go on to have duodenal ulcers over a 10- year
period.
2. Strength of the relationship.
• Helicobacter pylori is found in at least 90% of patients with duodenal ulcer.
50
3. Dose-response relationship.
• Density of Helicobacter pylori per square millimeter of gastric mucosa is
higher in patients with duodenal ulcer than in patients without duodenal ulcer
4. Replication of the findings.(consistency)
• Many of the observations regarding Helicobacter pylori have been
replicated repeatedly
5. Consideration of alternate explanations.
• Data suggest that smoking can increase the risk of duodenal ulcer in
Helicobacter pylori-infected patients but is not a risk factor in patients in
whom Helicobacter pylori has been eradicated
51
6. Biologic plausibility.
• Helicobacter pylori also induces mediators of inflammation.
• Helicobacter pylori-infected mucosa is weakened and is susceptible to the
damaging effects of acid.
7. Cessation of exposure.
• Eradication of Helicobacter pylori heals duodenal ulcers at the same rate as
histamine receptor antagonists.
52
8. Specificity of the association.
Prevalence of Helicobacter pylori in patients with duodenal ulcers is 90% to
100%.
References
Park’s Text book of Preventive & Social Medicine. 25th ed.
Community medicine with Recent advances by A.H.Suryakantha
Textbook of Community Medicine by Sunder Lal, Adarsh,
Pankaj. 6th ed
Thank You….
54

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Association & Causation

  • 1. Association & Causation 1 Dr. Ravi Prakash JR-III Dept. of Community Medicine Katihar Medical College 1
  • 2. Why is Association & Causation important?  To decide if a factor A causes disease B or not!  Is the link true or only facile?  Is it true or by chance?  If we know the cause(s) we can cure/treat /prevent/minimize the illness. (in a patient or the society) 2
  • 3. Association & Causation Association  Relation between two or more variables  Generally found in snapshot (cross-sectional) studies  Relationships can be positive or negative  Correlation! (factors moving together– like poverty and under nutrition) Causation  A variable (s) lead to another variable that is dependent/ outcome/ event/disease  So it suggests Etiology of disease  We need analytical studies to find out/prove cause(s) 3
  • 4. Associatio n Defined as occurrence of two variables more often than would be expected by chance. An association is present if probability of occurrence of a variable depends upon one or more variable. 4
  • 5. CAUSATION Precipitating Factors Predisposing Factors Enabling Factors Reinforcing Factors Age, Sex, Previous Illness Exposure to agent Low SEC, malnutrition Repeated Exposure Factors involved in Causation 5 CAUSE - an event, condition, characteristic (or a combination) which plays an important role / regular / predicable change in occurrence of the outcome (e.g. smoking and lung cancer)
  • 6. TYPES OF ASSOCIATION 1. SPURIOUS ASSOCIATION 2. INDIRECT ASSOCIATION 3. DIRECT (Causal) ASSOCIATION A. One-to-One Causal association B. Multi-Factorial Causation 6
  • 7. Pyramid Of Associations Causal Non-causal Confounded Spurious Positive /negative Raj Bhopal : Cause and effect: the epidemiological approach 7
  • 8.  Positive:Occurrence of higher value of a predictor variable is associated with occurrence of higher value of another dependent variable.  Negative: Occurrence of higher value of a predictor variable is associated with lower value of another dependent variable. Ex - Female literacy and IMR 8
  • 9.  Causal: Independent variable mustcause change in dependent variable. Ex – salt intake and hypertension  Non-causal: Non-directional association between two variables. Ex – alcohol use and smoking 9
  • 10. Spurious Association Spurious (not true) association •Not real, only apparent Example1: A study in UK of 5174 births at home and 11156 births at hospitals showed perinatal mortality rates of 5.4/1000 in home birth and 27.8/1000 in hospital births. (but this is spurious) Exapmle2: Fire and Fire Brigade may be found together in a snapshot--but Fire brigade is not the cause of FIRE. 10
  • 11. SPURIOUS ASSOCIATION  Some observed associations b/n a suspected factor and disease may not be real This Fallacy of presumption arises when two variables are improperly compared (due to Bias). PMR Home Deliveries (5174) Perinatal Mortality Rate Hosp Deliveries (11,156) 27.8 / 1000 5.4 / 1000 11
  • 12. INDIRECT ASSOCIATION  It is a statistical association between a characteristic of interest and a disease due to the presence of another factor i.e. common factor (confounding variable) 12
  • 13. E- Goitre Altitude Iodine Deficiency (Confounding Factor) Yudkin & Roddy’s wrong hypothesis on Sucrose and CHD association (Smoking is the Confounder). Jacob Yerushalamy identified the association b/n Smoking and Low birth weight babies is due to Confounding. 13
  • 14. 14
  • 16. DIRECT ASSOCIATION A. One-to-One Causal Relationship This model suggests that two factors (A & B) exhibit one to one relationship, if – Change in A is followed by Change in B. Cause (A) Effect (B) 16
  • 17. DIRECT ASSOCIATION A. One-to-One Causal Relationship This model suggests that two factors (A & B) exhibit one to one relationship, if – Change in A is followed by Change in B. Cause (A) Effect (B) Paramyxo Virus Measles 17
  • 18. KOCH’S POSTULATES (Germ Theory of Disease) Hemolytic Streptococci 1. Necessary, and 2. Sufficient. But this model does not fit well for many diseases, like in Tuberculosis, tubercle bacilli is clearly a necessary factor, but its presence may or may not be sufficient to produce the d/s.  A Single Factor may produce several Outcomes. Erysipelas Scarlett Fever Tonsillitis 18
  • 19. B. Multifactorial Causation In Several Modern Diseases, more than one factor is implicated in the Web of Causation. Eg: Both Asbestos exposure and Smoking cause Lung Cancer independently. As our Knowledge on disease increases, we may discover a common biochemical event, which can be altered by each of these factors 19
  • 20.  Multiple factor leads to the disease.  Common in non-communicable diseases  Alternative causal factors each acting independently. Ex: In lung cancer more than one factor (e.g. air pollution, smoking, heredity) can produce the disease independently. Either the causes are acting Independently OR Cumulatively 20
  • 21. Smoking Air pollution Reaction at cellular level Lung cancer Air pollution Reaction at cellular level Lung cancer + Exposure to asbestos Independently Exposure to asbestos Cumulatively Smoking + 21
  • 23. General Models of Causation  The most widely applied models are: – The epidemiological triad (triangle), – The web – The wheel and – The sufficient cause and component causes models (Rothman’s component causes model) 23
  • 24. Epidemiological triad Agent Factors Physical Agents Chemical Agents Biological Agents Nutritional agents Host Factors Socio-demographic Factors Psycho-social Factors Intrinsic Characteristics Environmental Factors Physical Environment Biological Environment Social Environment 24
  • 26. Web of Causation - CHD CHD 26
  • 27. Rothman’s Component Causes and Causal Pies Model • Rothman's model has emphasised that the causes of disease comprise a collection of factors. • These factors represent pieces of a pie, the whole pie (combinations of factors) are the sufficient causes for a disease. • It shows that a disease may have more than one sufficient cause, with each sufficient cause being composed of several factors 27
  • 28. • The factors represented by the pieces of the pie in this model are called component causes. • Each single component cause is rarely a sufficient cause by itself, But may be necessary cause. • Control of the disease could be achieved by removing one of the components in each "pie" and if there were a factor common to all "pies“ (necessary cause) the disease would be eliminated by removing that alone. A U B C N 28
  • 29. A U B C N Known components (causes) – A, B, C Unknown component (cause) - U N – Necessary cause Known components causes + Unknown component cause = Sufficient cause + Necessary cause 29
  • 31. If a relationship is causal, four types of causal relationships are possible: (1) Necessary And Sufficient (2) Necessary, But Not Sufficient (3) Sufficient, But Not Necessary (4) Neither Sufficient Nor Necessary 31
  • 32.  A factor is both necessary and sufficient for producing the disease.  Without that factor, the disease never develops and in the presence of that factor, the disease always develops Types of causal relationships I: Each factor is both necessary and sufficient FACTORA DISEASE 32 Necessary and Sufficient
  • 33. Necessary, But Not Sufficient  Each factor is necessary, but not, in itself, sufficient to cause the disease .  Thus, multiple factors are required, often in a specific sequence.  Ex: Carcinogenesis is considered to be a multistage process involving both initiation and promotion. A promoter must act after an initiator has acted. Action of an initiator or a promoter alone will not produce a cancer. 33
  • 36. Sufficient But Not Necessary  The factor alone can produce the disease, but so can other factors that are acting alone  Either radiation or benzene exposure can each produce leukemia without the presence of the other.  Even in this situation, however, cancer does not develop in everyone who has experienced radiation or benzene exposure, so although both factors are not needed, other cofactors probably are. Thus, the criterion of sufficient is rarely met by a single factor. 36
  • 38.  A factor by itself, is neither sufficient nor necessary to produce disease  This is a more complex model, which probably most accurately represents the causal relationships that operate in most chronic diseases. Types of causal relationships: IV. Each factor is neither sufficient nor necessary 38 Neither Sufficient Nor Necessary
  • 39. – Temporal association – Strength of association – Specificity of association – Consistency of association – Biological plausibility – Coherence of association 39 Additional criteria for judging causality
  • 40. Temporal association  The causal attribute must precede the disease or unfavorable outcome.  Exposureto the factor must have occurred before the disease developed.  Length of interval between exposure and disease very important.  Its more obvious in acute disease than in chronic disease. 40
  • 41. Temporal relationship (Relationship with time) • Cause must precede the effect. o Drinking contaminated water -occurrence of diarrhea. o However in many chronic cases, because of insidious onset and ignorance of precise induction period, it become hard to establish a temporal sequence as which comes first -the suspected agent or disease. 41
  • 42. Strength Of The Association  Relationship between cause and outcome could be strong or weak.  With increasing level of exposure to the risk factor an increase in incidence of the disease is found. • Strength of association can be estimated by relative risk. • Relative risks/Odds ratio greater than 2 can be considered strong • Larger the relative risk, greater the likelihood of a causal association. 42
  • 43. Dose-Response Relationship ( The Biological gradient )  As the dose of exposure increases, the risk of disease also increases  If a dose-response relationship is present, it is strong evidence for a causal relationship.  However, the absence of a dose-response relationship does not necessarily rule out a causal relationship.  In some cases in which a threshold may exist, no disease may develop up to a certain level of exposure (a threshold); above this level, disease may develop 43
  • 44.  The causal relationship of cigarette smoking and lung cancer has been based on three points. Relative risk Dose-response relationship Decrease in risk on cessation of smoking 44
  • 45. Biologic Plausibility Of The Association  The association must be consistent with the other knowledge (viz mechanism of action, evidence from animal experiments etc).  Sometimes the lack of plausibility may simply be due to the lack of sufficient knowledge about the pathogenesis of a disease, so the criterion of biological plausibility should not be applied rigidly.  It is difficult to demonstrate where the confounder itself exhibits a biological gradient in relation to the outcome. 45
  • 46. e.g. – cigarette smoking and lung cancer hypothesis is biologically plausible. Food intake and cancer are interrelated is an old one. Positive association of intestine, rectum, and breast cancer is biologically logical. 46
  • 47. Consistency Of The Association  Consistency is the occurrence of the association at some other time and place repeatedly.  Repeated observation of an association in different populations under different circumstances.  Example: consistent association between lung cancer and cigarette smoking – 50 retrospective study and almost 9 prospective studies. 47
  • 48. Specificity Of The Association  Specific exposure is associated with only one disease.  Specificity implies a one to one relationship between the cause and effect.  It’s the most difficult to occur for 2 reasons:  Single cause or factor can give rise to more than 1 disease  Most diseases are due to multiple factors.  Ex: Smoking is associated with many diseases. • Not everyone who smokes develops cancer • Not every one who develop cancer has smoke 48
  • 49. Coherence of the association  Based on available evidence or should be coherence with known facts that are thought to be relevant.  i.e. historic evidence of rising consumption of tobacco in form of cigarette and rising incidence of lung cancer are coherent. 49
  • 50. Deriving causal inferences: example Assessment of the Evidence Suggesting Helicobacter pylori Ulcers as a Causative Agent of Duodenal 1. Temporal relationship. • Helicobacter pylori is clearly linked to chronic gastritis. About 11% of chronic gastritis patients will go on to have duodenal ulcers over a 10- year period. 2. Strength of the relationship. • Helicobacter pylori is found in at least 90% of patients with duodenal ulcer. 50
  • 51. 3. Dose-response relationship. • Density of Helicobacter pylori per square millimeter of gastric mucosa is higher in patients with duodenal ulcer than in patients without duodenal ulcer 4. Replication of the findings.(consistency) • Many of the observations regarding Helicobacter pylori have been replicated repeatedly 5. Consideration of alternate explanations. • Data suggest that smoking can increase the risk of duodenal ulcer in Helicobacter pylori-infected patients but is not a risk factor in patients in whom Helicobacter pylori has been eradicated 51
  • 52. 6. Biologic plausibility. • Helicobacter pylori also induces mediators of inflammation. • Helicobacter pylori-infected mucosa is weakened and is susceptible to the damaging effects of acid. 7. Cessation of exposure. • Eradication of Helicobacter pylori heals duodenal ulcers at the same rate as histamine receptor antagonists. 52 8. Specificity of the association. Prevalence of Helicobacter pylori in patients with duodenal ulcers is 90% to 100%.
  • 53. References Park’s Text book of Preventive & Social Medicine. 25th ed. Community medicine with Recent advances by A.H.Suryakantha Textbook of Community Medicine by Sunder Lal, Adarsh, Pankaj. 6th ed