Epidemiology (2009)

Outline

Unit 1. IntroductionUnit 2. Measures of EpidemiologyUnit 3. Methods of StudyUnit 4. Disease ScreeningUnit 5. Descriptive EpidemiologyUnit 6. Investigation of an epidemicUnit 7. Ecological StudyUnit 8. Cross-Sectional Study Unit 8. Cohort StudyUnit 10. Case-Control StudyUnit 11. Intervention StudyUnit 12. Variability and BiasUnit 13. Interpretation of Epidemiologic LiteratureUnit 14. Readings

Reference:

– 陳建仁。流行病學 原理與方法。聯經出版社。1983。Rothman and Greenland. Modern Epidemiology. 2nd Edition. Lippincott-Raven. Philidelphia. 1998.

有學習問題請聯絡：06-2785123轉3118 或 suhsing@mail.cjcu.edu.tw李素幸老師

1

Unit 1. Introduction

Epi – among (Greek)Demos – people (Greek)Logos – doctrine (Greek)

Epidemiology: Definition: Epidemiology is the study of disease (injury, disability or death) occurrence in human populations. The primary units of concern are groups of persons, not separate individuals. (研究人類群體間之疾病(傷害、殘障、死亡)發生；主要研究單位係以一群人為主，而非單一個體。)

近代醫學的領域逐漸發展成三大類：一為基礎醫學，它提供衛生保健及疾病治療有關的基本知識，如解剖學、生理學、病理學、藥理學、營養學、生物化學、微生物學、遺傳學、免疫學等學科。二為臨床醫學，利用基礎醫學的各項知識與原理來診斷和治療病患。三為預防醫學，目地在於預防疾病的發生，流行病學即屬之。

1、 流行病學史：Hippocrates (希波格拉底) – 醫學之父，著作「論空氣、水和地方」。在書中提到，研究醫學的人要考慮一年四季的變化及其可能帶來的影響，因為這些因素均會影響疾病的發生。

John Graunt (十七世紀)：首先將計量方法引入流行病學。1. 出版死亡公告分析

人數 男性 女性死亡 209,346 190,474出生 139,782 130,866

*男女出生與死亡比例相似

2. 人口中男女之比為14比13，死者間男女比例亦然。然而，根據多數醫師的觀 察，前來就診者女性約為男性的兩倍，為何如此？

2

3. 編製生命表 (Life Table)：觀察100 活產嬰兒，於滿六歲前死去 36 人

於其後之第1個10年內死去24人(16歲，餘40人) 於其後之第2個10年內死去15人(26歲，餘25人) 於其後之第3個10年內死去9人(36歲，餘16人) 於其後之第4個10年內死去6人(46歲，餘10人) 於其後之第5個10年內死去4人(56歲，餘6人) 於其後之第6個10年內死去3人(66歲，餘3人) 於其後之第7個10年內死去2人(76歲，餘1人)

William Farr (十九世紀英國)之貢獻：英國中央註冊處生命統計局局長。連續而有系統地記錄死亡訊息自此開始。1. Age-Specific Deaths (年齡別死亡率)2. Cause of Deaths (死因別)3. Investigation of occupational associated diseases (職業死因之觀察與比較)

a. 銼刀和鋸子之製造工，因吸入石頭和鋼鐵微粒，故而死亡率高，在45-65歲間死亡率更高。

b. 陶器製造業工人，最初加入時死亡率頗低，在達三十五歲時，死亡率躍升為常人之一倍，最後比酒吧老闆的死亡率高。

John Snow (十九世紀)：1. 觀察霍亂病人：觀察： 照顧霍亂病人者，未必得到霍亂，不照顧霍亂病人者，未必不得霍亂。結論： 霍亂非屬接觸傳染性疾病。

新假設：疑似與嘔吐物或排泄物污染所致

2. 倫敦廣場霍亂暴發事件觀察： 死者均居住散落在倫敦廣場附近，而且距離某一抽水機不遠處。行動： 下令拆除抽水機柄。

3

(Survi val Curve)存活曲線

0%

20%

40%

60%

80%

100%

0 6 16 26 36 46 56 66 76

( )年齡 歲

(%

)存活百分比

結果： 死亡人數銳減。新假設：與水源污染有關

3. 觀察自來水公司供水情形假設：與水源污染有關觀察：自來水公司S、B之供水情形結果：

人口數 霍亂死亡數 霍亂死亡率 水源*地區X 167,654 844 5.0 S地區Y 19,133 18 0.9 B地區Z 300,149 652 2.2 S+B

*S公司水源來自泰晤士河下游；B公司水源來自泰晤士河上游 結論：霍亂死亡率與水源具潛在相關 (生態性研究)

4. 驗證假設：在地區Z*沿戶訪視，得各戶自來水公司與患病死者資料水公司 供應人口數 霍亂死亡數 霍亂死亡率

S 98,862 419 4.2B 154,615 80 0.5

*利用地區Z 居民，得以控制社會經濟地位與生活環境 (橫斷式研究)結論： S公司水源來自受污染的泰晤士河下游，導致用戶感染霍亂死亡。

實驗性研究：1. 1747年，Lind (林德)以新鮮水果治癒壞血病2. 1796年，Jenner (珍納)以牛痘疫苗預防天花3. 1881年，Findlay (芬雷)證實黃熱病由蚊子傳播4. 1900年及1915年，Reed (瑞德)與Goldberger (哥柏格)證實維生素B和癩皮病有關

5. 1905年，Fletcher (弗列丘) 隨機分配精神病人食用暹邏米與印度米 (一年)食用人口數 腳氣病人數 腳氣病死亡數

暹邏米* 120 34 18印度米# 123 2 0

*碾米前未先行煮過的米 #碾米前煮半熟的米結論：煮成半熟而加以碾磨的米，具有預防腳氣病之功效。注意：人體試驗必須謹慎評估並遵行實驗道德。

6. 二次世界大戰後在自來水中加入氟以預防齵齒之試驗。

4

Unit 2. Measures of Epidemiology

Count (計數): Male and Female in ClassRatio (比/比率): express the relationship between two numbers in the form X:Y or x/y • kProportion (分率/比例): a specific type of ratio in which the numerator is included in the

denominator.

Male/Total or Female/Total

Measures can characterize:

1. One point in time: e.g., number of motorcycle accidents in 1/1/19992. A period of time: e.g., number of motorcycle accidents during 1/1/1999-12/31/1999a a. Average change per unit of time – a rate

b. Cumulative changes – a probability, or risk estimation

Rate: number of people that develop disease during the specified time period.Units of time (e.g., person-years) the people were capable of

developing the disease during the specified period

Risk/Probability = number of people that develop disease during the specified time period

Number of people at risk (at-risk: capable of developing the characteristics)

person-years: equivalent number of people who would have been at risk for one full year

for example: 1000 person-years equals:

People Time-at-risk (average)1000 1 year500 2 years250 4 years200 5 years100 10 years

Under the assumption that every person-year has the same risk for diseases, in fact, we know it is not true since a person-year contributed from a seventy year-old men is more vulnerable to diseases than a person-year contributed from a twenty year-old young men.

5

Risk and Rate Calculation:

1000 elderly identified January 1, 1990300 deaths during 1990

Risk (probability) of death = (300/1000)×1000= 300 (deaths per 1,000 persons)Rate of death = 300/(700 + 150) =300/850 (300/850) × 1000 = 352 (per 1,000 person-years)

Under the assumption that 300 deceased cases were dead at the time equally distributed in this one-year period.

In a five years observation, 1000 elderly identified January 1, 1990

First year 20 diedSecond year 30 diedThird year 30 diedFourth year 25 diedFifth year 50 died Total 155 died during the five year period, please calculate risk and rate?

Risk = 155/1000 = 0.155

Person-years: （粗計算法）

Year one Year two Year three Year four Year fiveDeath 20 30 30 25 50Person-Years 980+10=990 950+15=965 920+15=935 895+13=908 845+25=870

Total person-years = 990+965+935+908+870= 4668Rate = (155/4668) ×1,000 = 33 (per 1,000 person-years)

6

Prevalence depends on two factors

1. The number of people who have been ill in the past2. The duration of their illness

P = I × D (I × D) +1

I: Incidence (發生) ~ Disease prevention, migrationD: Duration (病期) ~ Treatment, Disease fatality

3. If the incidence and duration have both been stable over a long period of time, then this formula becomes P ∝ I × D

4. Seldom is prevalence of direct interest in etiological applications of epidemiologic research. Since prevalence reflects both the incidence rate and the probability of surviving with disease, studies of prevalence or studies based on prevalence cases yield associations that reflect the determinants of survival with disease just as much as the causes of disease. (病因研究中極少使用盛行，因盛行受疾病之發生與存活兩種因素影響，所得之結果亦含此二因素)

5. High prevalence does not necessarily signify high risk; it may merely reflect an increase in survival. Low prevalence may reflect a rapidly fatal process or rapid cure of disease as well as low incidence. (高盛行未必代表高危險，其可能因高存活所致；低盛行可能係因疾病致死性強或快速治愈)

( 陳建仁 p.102)

6. Prevalence is important, particularly in chronic disease, in determining workload, as it is a useful tool for the planning of facilities and manpower needs. (在慢性病防治中，盛行之調查將有助於估算防治計劃之人力與物力)

7. Periodic estimation of point prevalence is useful in tracking changes in disease patterns over time. Point prevalence can be determined by a series of cross-sectional surveys. (定期之盛行調查將有助於觀查族群中疾病的變動；點盛行可由橫斷調查法求得)

7

Incidence (發生)

Incidence rates are the fundamental tool for etiologic studies of both acute and chronic disease, since they are direct indicators of risk of disease. (為病因調查之基本工具，因其代表疾病之危險)

Certain basic requirements must met if incidence rates are to be calculated:a. Knowledge of the health status of the study population. There must be adequate

grounds on which to assess the health of individuals in a population and to classify people as “diseased” or “not diseased.” (必須區分疾病與健康狀況)

b. Time of onset. Determination of date of onset is necessary for studies of incidence. For chronic disease and cancer, the date of onset is defined by the date of definitive diagnosis. (必須知到疾病發作之時間)

c. Specification of numerator: number of persons vs. number of conditions. In certain circumstances, more than one event can occur to the same person within a stated time period. (分子為人或事件須區分清楚)

e.g., Number of people who developed a cold in one-year periodPeople at risk in one-year period

(The risk (probability) that any person will develop a cold in one year; usually if not specified we assume persons to be numerator)

Number of colds in one-year period People at risk in one-year period

(The number of colds to be expected among the group of people in a year)

d. Specification of denominator. The denominator should not include those who are not susceptible to the disease (not at risk). In a large population, this correction is not made due to practical problems. (Annual rates usually use the estimated midyear population). (有危險者得成為分母)

e. Period of observation. It is important to always state the definite time period.

8

Calculation: Study period: from January 1, 1990 to December 31, 1995

1990.1.1 1991 1992 1993 1994 1995 Dec 31,1995

A x x deadB ______ healthyC disease YDEFGHIJ xK x

Point prevalence of disease Y on the day of January 1, 1995 is ______ .Period prevalence of disease Y during the study period is _______ .Risk of disease Y during the study period is _______ .Rate of disease Y during the study period is _______ .

Exercise:有20000為男性參加某研究，在1999年1月1日加入時發現160人患有高血壓，經過一年的觀察後，在1999年12月31日測得參加者有100位新發生高血壓病患，再經過一年，在2000年12月31日再測得80位新發生的高血壓病患，在觀察的最後一年，2001年12月31日測得60位新發病的病患。（1） 請問在此研究族群中，三年觀察期間內的高血壓發生率(Incidence rate)為？（2） 請問在此研究族群中，三年觀察期間內的高血壓發生危險(risk)為？請問在此研究族群中，在1999年1月1日的高血壓盛行為？

9

Standardization of rates:

Crude Rate = total number of casesTotal person-time or population at risk

Standardization:1. Removes the distortion introduced by different age distributions across populations

(除去因年齡(或干擾)因素所造成之疾病或死亡率偏差)2. It provides the opportunity to examine disease rates while holding the effect of age

constant. (使群體間得以在年齡組成相同的情況下比較各別之疾病或死亡率)

e.g.,

Total number of lung cancer deaths

1990 population Crude death rate(per 1000)

Farming area 156 11,161 14.98Industrial area 122 4,700 25.96

Direct method: In the direct method, age-specific rates observed in two or more study populations are applied to an arbitrarily chosen population of known age structure referred to as a “standard” population. (在間接法中，將欲研究群體之特殊年齡死亡率與某群體(稱之標準群體)之年齡組成計算得來。)

In the farming area

Age 1990 Population

Number of lung cancer

deaths

Age-Specific death rate

( per 1000)

StandardPopulation Proportions

Age-standardized death rate (per

1000)<15 2348 2 0.85 0.288 0.24

15-29 4157 15 3.61 0.243 0.8830-39 1243 6 4.83 0.111 0.5440-49 959 15 15.64 0.120 1.8850-59 853 23 26.96 0.106 2.8660-69 772 34 44.04 0.074 3.2670+ 829 61 73.58 0.059 4.34

Total 156 14.0* Standard Population Proportions usually come from an arbitrarily chosen population

of known age structure referred to as a standard population. * Age-specific death rate = number of deaths at a specific age during a period/ average

population for this specific age during a period

In industrial area:

10

Age 1990 Population

Number of lung cancer

deaths

Age-Specific death rates(per 1000)

StandardPopulation Proportions

Age-standardized death rates (per

1000)<15 1015 0 0 0.288 0

15-29 1193 3 2.5 0.243 0.6130-39 441 3 6.8 0.111 0.7540-49 430 7 16.3 0.120 1.9650-59 449 15 33.4 0.106 3.5460-69 479 24 50.1 0.074 3.7170+ 693 70 101.0 0.059 5.96

Total 122 16.5

Indirect method:1. Indirect method is used to compare two populations, in one of which the age-specific

rates are not known or, if known, are excessively variable because of small numbers.(當比較之群體中有一特殊年齡別死亡率未知或因死亡數太少而不穩定時，則改用間接法。)

2. In this method, the more stable rates of the larger population are applied to the population of the smaller study group.(在間接法中，將較大群體之特殊年齡別死亡率運用在較小群體。)

3. Comparison of the number of expected deaths in the smaller population with the number actually observed yields a measure known as the Standardized Mortality Ratio (SMR).

SMR=Observed deaths/Expected deaths

Age Death rates in standard

population(per 1000)

1990 population in

industrial area

Expected number of

deaths

Observed number of

deaths

<15 0.62 1015 0.63 015-29 3.71 1193 4.43 330-39 5.52 441 2.43 340-49 13.43 430 5.77 750-59 36.71 449 16.48 1560-69 72.32 479 34.64 2470+ 83.83 693 58.09 70

Total 122.47 122

Standardized Mortality Ratio (SMR) = Observed number/expected number x 100Conclusion: (122/122.47) x 100 = 99

11

Age Death rate in standard

population(per 1000)

population in farming area

Expected number of

deaths

Observed number of

deaths

<15 0.62 2348 1.45 215-29 3.71 4157 15.42 1530-39 5.52 1243 6.86 640-49 13.43 959 12.88 1550-59 36.71 853 31.31 2360-69 72.32 772 55.83 3470+ 83.83 829 69.49 61

Total 193.24 156

SMR= (156/193.24) x 100 = 81

某人蒐集沿海地區四鄉鎮、臺北地區及全台灣地區的膀胱癌死亡和人口資料如下： 四鄉 鎮 台北 地區 台灣 地區

年齡 人口數膀胱癌死亡數

人口數 膀胱癌死亡數

人口數 膀胱癌死亡數

30 ~ 39 40,000 10 400,000 20 8,000,000 30040 ~ 59 30,000 20 400,000 50 8,000,000 700> = 60 30,000 30 400,000 250 6,000,000 2,000

(1)若以台北地區為標準群體，請問四鄉鎮地區的膀胱癌標準死亡比(SMR)為何？(2)若以台灣地區為標準群體，請以直接法計算台北地區之膀胱癌標準化死亡率？

12

Proportional Mortality Rate = number of deaths due to a particular cause(比例死因率/PMR) Total number of deaths

1. PMR is used when the living population at risk for the observed deaths can not readily be enumerated (母群體未知，僅知各別死因數目)

2. In the hope that a high proportional mortality rate for a particular condition reflects a high true mortality rate for that condition.(以PMR來估計各死因之死亡率高低)

3. A caveat while applying PMR, a high proportional mortality can also be caused by a deficiency of deaths from other cause.(注意：高PMR往往受其他死因所左右)

Policeman Farmer Industry Fisherman Others1994 Deaths 40 20 100 40 60

PMR 0.15 0.08 0.38 0.15 0.231995 Deaths 80 20 100 40 60

PMR 0.27 0.07 0.33 0.13 0.2

Policeman Farmer Industry Fisherman Others1995 Deaths 40 20 100 40 60

PMR 0.15 0.08 0.38 0.15 0.231996 Deaths 40 20 80 40 10

PMR 0.21 0.10 0.42 0.21 0.051997 Deaths 80 40 160 80 20

PMR 0.21 0.10 0.42 0.21 0.05 If the populations among each occupation have not changed in these years

Policeman Farmer Industry Fisherman OthersPopulation 1000 10,000 40,000 5000 100,000

1995 Deaths 40 20 100 40 60Death Rate 0.04 0.002 0.0025 0.008 0.0006

1996 Deaths 40 20 80 40 10 Death Rate 0.04 0.002 0.002 0.008 0.0001

1997 Deaths 80 40 160 80 20Death Rate 0.08 0.004 0.004 0.016 0.0002

13

Rate Difference: By subtracting the smaller from the larger, one may obtain the magnitude of the rate difference. (率差)

Attributable Risk : the difference between two incidence rates.(可歸因的危險)

e.g., in Hammond’s (1996) study of smoking and mortality:

Lung cancer mortality rate

in nonsmokers aged 55-69= 19 per 100,000 person-yearsin smokers age 55-69= 188 per 100,000 persons-years

Rate difference = 169 per 100,000 person-years

Smoking cigarette produce 169 lung cancer cases per 100,000 person-years

Attributable risk percent ( 危險百分率 ) (etiologic fraction (病因分率) or attributable fraction): is the difference between rates between the exposed and non-exposed divided by the rate in the exposed

169 per 100,000 person-year/188 per 100,000 person-years = 169/188 = 0.9

Smoking produced 90% of the lung cancer cases among smokers.Among smokers, 90% of the lung cancer were attributable to smoking.

Population Attributable Risk (PAR; 族群可歸因的危險): Rp - Runexp

Population Attributable Risk Percent (PAR%;族群病因分率): (Rp - Runexp )/Rp

Eg., 自1980年起調查200,000 名勞工抽煙史，並將其抽煙情形分為抽煙者、已戒煙者、從不吸煙者等3組作追蹤，十年後發現：

抽煙情形 肺癌人數 觀察人年數吸煙者 121 660,000已戒煙者 25 200,000從不吸煙者 62 1060,000總和 208 1,920,000

請問抽煙行為在抽煙者中所造成的危險為？在族群中所造成的危險為？

14

Unit 3 Methods of Study

Observational (觀察性) versus Experimental (實驗性) versus Quasi-Experimental (半實驗性)

Descriptive (描述性) versus Analytic (分析性) Prospective (前瞻性) versus Retrospective (後瞻性)

Experimental versus Quasi-Experimental versus Obervationala. In experimental study, the investigator actively intervenes and makes one

variable change and then sees what happens to the other. (在實驗研究中,研究者主動的干預和改變某一變數,再視其對其他因素有何影響。)

b. The sole difference between experimental and quasi-experimental is that quasi-experimental study does not have the control on assigning subjects to exposed or non-exposed group (lack of randomization). Subjects are usually self-selected in assigning themselves to exposed or non-exposed group; or sometimes the researchers arbitrarily assign subjects into groups. And, sometimes, there is no control group at all. (半實驗性的研究中,個案並不經由隨機方式分組；分組可能隨個案意願或由研究者隨意分組。有時實驗中並沒有對照組。)

c. In observational study, natural is allowed to take its course, and changes or differences in one characteristic are studied in relation to changes or differences in the other, if any. (在觀察研究時,隨自然法則,觀察某事件的變異是否與他事件的改變相關。)

Experimental: manipulate study factor; randomize study subjects Quasi-experimental: manipulate study factor; no randomization of study subjects Observational: no manipulation of study factor; no randomization of study subjects

ExperimentalAdvantages: control over extraneous factors; the results can make a strong statement of the cause

and effect relation

Limitations: Over control of extraneous factors; Not natural setting; the result is hard to generalized to the general population, e.g., Practical issues of implementation

a. Randomization not ethical: sometimes it’s not ethical to randomize persons to risk factors

b. Design that is not feasible: sometimes, doing a community intervention, to see if sunscreen can protect skin cancer; however, the control being contaminated by their co-workers, the television, the magazine.

Quasi-Experimental: Studies may have experiment and control groups, but subjects are not randomized into

each group.

15

Studies may have only one group (experiment group), there is no control group for comparison. People usually compare before and after using certain indexes. We don’t know the outcome of not implement; we only know the outcome of implement.

Advantages: More feasibility and less expensive than experimental study

Limitations: Less control of extraneous factors

Experiment

Experiment

Observational study falls into two categories: descriptive

a. Characterize a situation. (描述某事件)b. Descriptive approach characterizes the distribution of something but does not

necessarily try to explain the underlying reasons for the distribution. (意在描述,不在解釋其現象。)

c. Usually involve the determination of the incidence, prevalence, and mortality rates for diseases in large population groups according to basic group characteristics, such as age, gender, race (demographics) and geographic data. (通常依群體的特徵,如年齡、性別、種族及地理特性,計算此一群體中某病之發生率、盛行率及死亡率。)

Analytica. Explain why the situation occurs: have at least one exposure and one outcome.

(解釋某事件發生之原因，至少有一因素為暴露，有一為因果。)b. The staring point for an analytic study is often a descriptive finding that raises

certain questions or suggests certain hypotheses that require further investigation. (分析性研究通常起始於描述性研究，發現疑問和假說而進一步探索原因。)

Descriptive studies

16

Analysis of results Model-building and formulation of hypotheses

Analytic studies to test hypotheses

Prospective versus Retrospective

Exposures Outcomes

Prospective

Retrospective

a. Prospective study: Exposure measurements are made before the outcomes occur. (暴露的觀察時間早在因果出現之前。)

b. Retrospective study: Exposure measurements are made after the outcomes occur. (暴露的觀察時間在因果出現之後。)

c. Early writers referred to cohort studies as prospective studies and to case-control studies as retrospective studies. However, during current epidemilogical study design, both cohort study and case-control study can be prospective and retrospective.

17

Unit 4. Descriptive Epidemiology

Descriptive Epidemiology: Description of the exposures and outcomes Person/who Time/when Place/where

Purpose of descriptive studies:a. Alerting the medical community to what types of persons are most likely to be affected

by a disease, where the disease will occur, and when. (提供醫界有關疾病的預警。)b. Assisting in the rational planning of health and medical care facilities. (協助策劃健康及醫療設施。)

c. Providing clues to disease etiology and questions or hypotheses for further fruitful study. (提供有關疾病之病因、問題及假說。)

18

Unit 5. Ecological study (生態研究):

a. Observation of disease and exposure on the group basis.

D D

E a b a+b

E c d c+d

a+c b+d N

In ecological study, we know the data by group: a+c, b+d, a+b, and c+d. We do not have information on individual cells: a,b,c,and d.

Ecological Fallacy (生態謬誤): The failure of expected ecological effect estimates to reflect the biologic effect at the

individual level. (生態研究結果無法顯示出真正個人層次之生物效應) Examples: Researchers found suicide rate is associated with areas where Catholics

lives (1951). Latter, some researchers found that in these area also lives many minorities with very high suicide rate, in contrast, Catholics has low suicide rate.

Summary of Ecologic Studies

Advantages: Good for Generating hypotheses Inexpensive Quick and simple

Limitations: Population information may not apply to individuals Difficult to derive precise estimates of exposure and/or disease No control for extraneous factors (confounding)

19

Unit 6. Cross-Sectional Study (橫斷研究)

a. Includes all persons in the population at the time of ascertainment or a representative sample of all such persons as subjects. (研究個案包括資料收集時群體內之所有人或具代表性之一群人)

b. Exposure status and disease status are measured at one point in time or over a short period of time in the study subjects. (暴露情形與疾病狀態在同一點時間上收集)

c. A cross-sectional study conducted to estimate prevalence is called a prevalence study.

In a nutshell, select N then determine this distribution of E and D

D D

E a b a+b

E c d c+d

a+c b+d N

Summary of Cross-Sectional StudiesAdvantages:a. Particularly useful for

1. Frequent diseases of long duration (常見且病程長之疾病)2. Determining characteristics of a population (了解群體之特性)3. Estimating the prevalence of a disease (估計疾病之盛行)4. Generating hypotheses of exposure – disease relationships (建立暴露與疾病之假說)

b. Generalizability, due to the ways that the subjects are recruited into the study. (通常取樣自某一群體，故對此群體而言代表性佳)

Limitation:a. Not useful for rare diseases or diseases with short duration (不適於研究較罕見之疾病)

b. Cause-effect relationship tenuous (temporality); it may be impossible to determine which came first. (e.g., do people in low social classes have higher prevalence rates of many mental illness than do people of higher social classes, or do people migrate down the social class scale once they become mentally ill and are therefore found in the lower social classes at the time a study is done?) (在因果推論上之時序性無法成立)

c. For disease is in remission may be falsely classified as not having the disease. (時好時壞之疾病可能會被誤以為沒有病者)

d. People either recover or die from a disease quickly has less of a chance of being included in the disease group. If characteristics of persons whose disease is either of short duration or rapidly fatal are different from those whose disease is of long duration, then the exposure-disease association observed in a cross-sectional study will misrepresent the association of exposure with incidence. (所發現之個案較傾向於病

20

程較長者，如果病程進展較短者(痊癒或死亡者)之特徵與較長者有所不同，則此研究之暴露與疾病發生之因果推論會遭誤導(因加之預後因素)。

21

Unit 7. Cohort Study (世代研究)

D D

E a b a+b

E c d c+d

a+c b+d N

Research strategies:a. Prospective (前瞻法、追蹤法) – The investigator collects information on the exposure

status of the study subjects at the time the study begins, and identified new cases of disease (or deaths) from that time on（研究開始時，研究者先收集所有研究群體之暴露資料，然後跟隨著收集疾病發作之情形）

b. Retrospective (後瞻法、回溯法) – The investigator identifies the exposure characteristics of a cohort in the past and then reconstructs the subsequent disease experience up to some defined point in the more recent past or up to the present time. (研究者先確認某群體過去的暴露資料，然後收集暴露後過去與目前之疾病發作情形)

c. Retrospective cohort studies have some distinct advantages over prospective cohort studies; in particular, they can be completed in a much more timely fashion and are therefore considered less expensive. (回溯法能縮短時間完成，故較不昂貴)

d. In Retrospective cohort studies, the investigator may have the problems in determining exposures, while in prospective cohort studies, the investigator can actually measure the exposures thoroughly. (在回溯法暴露狀態可能不易決定，在前瞻法中暴露可實測得之)

Sources of cohorts(世代的種類):a. Special exposure groups (特殊世代)

1. High occupational exposure2. Smokers3. Persons with unusually high or low physiologic measurement, e.g., cholesterol or blood pressure (具有特別高或低檢驗值者)

b. Special resource group (特殊資料來源者)1. Prepaid medical care plans (保險資料)2. Physicians 3. Insured persons4. Veterans5. College graduates

c. Geographically defined group (屬於同一地區者)1. Framingham, Massachusetts

Selection of comparison groups:

22

a. Internal comparison group (內部比較組): One group is initially defined and then divided into exposure categories (在觀察的群體內依暴露情形而區分暴露與非暴露群)(usually, relative risk and mortality rate are calculated)

b. External comparison group(外來比較組): When there is no non-exposed sub-group existed in this cohort, a external population is sought, e.g., general population, another factories, etc. (usually, mortality rates are compared; rate ratios or SMR) (當觀察群體內無法區分暴露狀態時，可採另一無暴露之群體作比較)

c. Multiple: A combination of the above (Internal and External comparison groups). Should the comparison groups give different results, then the investigator must try to find out why the results are different. (內部及外來比較組均採用)

d. Healthy-worker effect (健康工人效應): Workers are on the average healthier than the general population and would be expected to have lower disease rates. (工作者平均較一般大眾健康，同時疾病率較低)

e. Note that the possibility of self-selection into the initial exposed and unexposed groups always needs to be considered. (自我選擇性的暴露情形應納入考量)

f. Careful thought must enter into the choice of the comparison group and of the measurements to be made on all cohort members so that either the unexposed cohort members are firmly believed to be comparable to exposed cohort members, except for the exposure, in the likelihood of developing the disease. (選擇比較組時應仔細考量，非暴露組是否除了非暴露因子外，其他特性均與暴露組相似)

Sources of Information on Exposure (暴露資料來源):a. Available Records (現成記錄)b. Interviews (訪談)c. Medical examination (醫療記錄)d. Measures of the environment (環測資料)

Summary of cohort studies:a. Advantages

1. Direct determination of risk or rate (可以得到risk 與rate)2. Stronger evidence of exposure and disease association(提供暴露與疾病間的有力證據)

3. Provides evidence about lag time between exposure and disease (提供暴露與疾病間的時效性證據)

4. Easier to generalize findings (發現容易推論利用)b. Limitations:

1. Take a long time (耗時)2. Difficult to implement and carry out (較難實施與完成)3. Big dimes (耗資)4. Lost to follow-up (研究對象易失蹤)

23

Relative Risk (RR)/Risk Ratio: a ratio obtained by dividing risk of one group (usually exposed group) by risk of another group (usually unexposed group) (相關危險度)

DiseaseYes No Total

a+bExposed

Exposure c+d

Non-exposed

RR = a/a+bc/c+d

e.g., association between use of artificial sweeteners and bladder cnacer.

Bladder CancerYes No Total

4130Exposed

Artificial sweeteners 7222

Non-exposed

RR = 130/4130 = 1.02222/7222

Those who exposed to artificial sweeteners have 2% higher chance than those who did not to develop bladder cancer.

The risk of developing bladder cancer for those who exposed to artificial sweeteners compared to those who did not is 1.02.

Very close to 1.0, that means there is probably no association between artificial sweeteners and bladder cancer.

Be cautious in applying 1.0 cut point.

24

a

c

b

d

130

222

4000

7000

Unit 8. Case-control study（病例對照研究）

a. Persons with a given disease (the cases) and persons without the given disease (the controls) are selected; the proportions of cases and controls that have certain background characteristics are then determined and compared. (在研究開始時，認定一群有病者與一群無病者，調查這兩組群體過去的暴露特質，然後作比較)

b. In a nutshell, From effect to cause

D D

E a b a+b

E c d c+d

a+c b+d N

d. Sources of cases (個案來源):1. Ideally : All incident cases in a defined population in a specified time period; e.g., a tumor or disease registry, or a Vital Statistics Bureau (個案可來自某特定群體的某一時間，如疾病通報資料庫)2. In the real world : Logistics may restrict case selection to one or a few medical facilities. (現實中，個案可能來自某些醫院的病患)

e. Caveats in selection of cases(個案選擇時應注意事項):1. Representativeness of the cases derived from special care facilities (來自這些特殊照顧機構的個案應具有代表性)2. Prevalent cases make it difficult to separate characteristics that are causal or consequential; usually, incident cases are used in the study. (應採用發生個案)

f. Selection of Controls (對照之選擇):1. Ideally : Should have the same characteristics as the cases, except for the exposure of interest. (除了研究之暴露因子，應與個案具相同之特徵)2. In the real world : rarely achieved… (現實中很少達到)

g. Sources of Controls:1. Populations: Total population, random sample (自群體中隨機抽樣)2. Patients from same hospital as the cases (同來自一家醫院的其他病患者)3. Relatives of cases: Spouses, siblings (病人的親族)4. Associates of cases: Friends, co-workers, neighbors (病人的熟人)

Sources of Controls:a. Population:

1. Advantage: More representative

25

2. Limitation: Expensive and low participation possible

b. Patients from same hospital as the cases:1. Advantage: Cheap, quick, more likely to participate2. Limitation: May not be representative

c. Relatives of cases:1. Advantage: Good way to control for other variables, e.g., socioeconomic status,

education, ethnic status2. Limitation: Expensive and time consuming; may end up controlling for an

important (unidentified) risk factor

26

Matching (配對)a. The pairing of one or more controls to each case based on certain characteristics. (依某些因素，將對照與個案配對成一樣)

b. Matching in case-control study will introduce bias into the study. (個案對照中的配對會導致偏差；世代研究中之配對則不會))

c. To enhance study precision. (可增加研究之精確度；confidence interval 範圍會減小)

d. Variables selected in matching should be controlled latter in the data analysis. (凡被選擇為配對之因子應在研究分析中加以控制)

Summary of case control studies:a. Quickb. Easyc. Relatively inexpensived. More easily repeatede. Particularly useful for rare diseases

Limitations:a. Difficult to know representativeness of the cases and controlsb. In some cases, may not provide a direct measure of risk, only odds ratio can be

obtained; in some cases, if the population served as controls, rate can be obtained. c. Possibility of introduction of bias: selection bias, follow-up bias, information bias

27

Odds Ratio: a technique for estimating relative risk (勝算比)

Disease statusCase Control Total

a+bExposed

Exposure c+d

Non-exposed

OR = a/b or ad/bcc/d

e.g.,

Heart AttackCase Control Total

7835Exposed

Physical inactive5192

Non-exposed

OR = 307/7528 = 1.69122/5070

If it is a rare disease, OR is close to RR. >1 positive correlation (risk factor)=1 No correlation<1 Negative correlation (protective factor)

95% confidence intervalincluding 1 not statistically significant

Rate Ratio: Rate (usually incidence rate) for exposed dividing the rate for non-exposed.

28

a

c

b

d

307

122

7,528

5,070

Unit 9. Intervention Studies (介入性研究):

To test efficacy of a preventive or therapeutic measure.a. Clinical trial (臨床試驗):

1. The focus is on individuals2. Duration ranges from days to years3. Generally restricted to a highly selected population

b. Community trial(社區試驗)：1. The focus is on group or community outcomes2. Longer duration (> 6 months)3. Usually primary prevention

Clinical trial:

Selection of eligibles

29

Sample

Nonparticipants

Randomization

InterventionGroup

ControlGroup

Lost ToFollow-up

MeasureOutcome

MeasureOutcome

Population

Procedures to reduced bias in assessment of outcome in a clinical trial:a. Single blind design – Subject is unaware of intervention group

1. Informed consent already obtained2. Experimenter must treat and monitor all groups in a similar manner

b. Double blind design – Subject and experimenter are unaware of the group assignment1. Placebo or treatment agents come in a pre-assigned container2. All subjects treated and monitored in a similar manner

Summary of clinical trial:a. Advantages:

1. Greatest control over the study situation2. Randomization reduces confounding

b. Limitation:1. Control may lead to “artificial” setting, limit ability to generalize2. Ethical dilemmas

2.1. Withholding beneficial treatment2.2. When to stop because of side-effect

3. Adherence to protocols may be difficult to enforce4. Design may not be feasible

4.1. Manipulation of a psychosocial attribute (e.g., human behavior)4.2. Double blinding of a non-pharmacologic treatment (everyone can see who

gets what treatment, if the treatment if so obviously different, e.g., type of vegetables)

30

Community trial:

Randomly AssignTreatment

Summary of community trials:a. Advantages: Only way to directly estimate the realistic impact of a change in behavior

on the incidence of diseaseb. Limitations:

1. Less control than a clinical trial2. Unable to control for differences between communities with respect to

2.1. Racial composition2.2. Education level2.3. Age distribution

3. Dynamic population may lead to loss of demonstrated effect4. Non-intervention influences (e.g., volunteer groups, media) can impact on both

control and treatment communities (外來的干擾)

31

Observe Occurrence of Disease forA Specified Period of Time

Initiate Program Do Nothing

MeasureOutcome

Measure Outcome

PopulationB

PopulationA

Unit 10. Causality

Criteria for causality (因果關係之判定): to say one thing is a causal factor to a disease, this factor must meet the criteria:

temporal sequence (temporality) 時序性:

a. exposures should precede the event. (暴露應在因果前出現) b. the onset (發病) must occurred after the induction (誘導期) latency period

(潛伏期). c. Latency: The period from disease initiation to manifestation. Very often,

latency is the term applied to the time interval between exposure and disease manifestation or recognition.

d. Induction time: The period from first exposure to an agent or collection of agents to disease initiation.

‘Often time referred to as Latency period’

Induction Period Latency Period

First Exposure Disease Induced identification of disease

Latency period is often used in cancer research; while incubation time is usually applied in infectious diseases. They represent similar concept.

Consistency (一致性):a. a second condition that supports a causal interpretation of an

association is the repeated observation of the association under different conditions of study. (此因果相關應出現在不同的研究條件下)

b. in a variety of population, e.g., vegetable can prevent colon cancer, or garlic can reduce ….. in the news

c. in a variety of different types of studiesd. by a variety of investigators

Meta-analysis: focus on contrasting and combining results from different studies, in

the hopes of identifying consistent patterns and sources of disagreement among those results.(比較綜合各研究成果,希望能藉此認定某一一致的因果型態,同時並找尋各研究成果間不吻合的根源)

Is a statistical analysis of a collection of studies, especially an analysis in which studies are the primary units of analysis. (用統計的方法來分析這些研究成果,分析單位為每個各別的研究。)

32

strength of association (強度)a. The larger the value of the relative risk (相對危險), the less likely the

association is to be spurious. (相關危險度愈大者,其因果相關愈可能為真。)

biological gradient (生物性漸增趨勢)/dose-response relationship (劑量效應):a. Dose-response relationship: when the exposures had

increased the risk also increase. (當暴露增加危險亦隨之增加。)

Linear

Threshold (閥)

* Threshold – the lowest limit at which a stimulus become perceptible.

b. For dose, we have to consider its intensity(暴露強度)/ concentration, and duration (暴露時間).

c. in epi, we consider exposure from the environment of its concentration (air sampling), or hour of exposure/or year of exposure (for cancer), but the concentration can also from blood test. Blood test is most accurate, but without this luxury, we usually detect the exposure from breathing air and hour of work, or location of work from the contaminated sources.

Specificity (特殊性):a. A cause is ‘specific’ to an effect if the introduction of the

putative causal factor is followed by the occurrence of the effect. (whenever A occurred, the disease occurred) E.g., infectious disease. (假若某可疑因子之出現會有某一因果之隨後發生,則此因子具有特殊性。)

b. However, multiple causes and multiple effects are more often occurred. E.g., radiation exposure may cause leukemia, cataracts, thyroid cancer, lung cancer…), smoking and asbestos from occupational exposures can all cause lung cancer

c. And for chronic disease, it often caused by many factors, e.g., genetic reasons and life styles.

biological plausibility (生物上的贊同性):a. can be support by biological knowledge, not against knowledge from lab

experience. (為生物知識所支持,不違實驗結果。)

Unit 11. Variability and Bias

33

Statistical Measures of Association:a. General:

1. P-value: The probability that the difference between the value of a variable in your sample and the true population value could have occurred by chance alone1.1. A p-value of 0.05 implies that if the same study was done 100 times, the difference observed would have occurred by chance alone only 5 times.

2. Confidence Interval (CI) – A measure of uncertainty about a parameter estimate (a mean, OR, RR, incidence rate, etc)2.1. Utility: The 95% confidence interval contains the “true” population estimate

95% of the time.2.2. Translation: If you sample 100 times, the 95%CI will contain the true

estimate 95 times.2.3. CI are a function of the variability of the data and the sample size

3. Correlation Coefficient r – A quantitative measure of the degree of linear association between variables.3.1. If r > 0, the variable are said to be posively correlated3.2. If r < 0, the variables are said to be negatively correlated. As X increases,

Y decreases, or as X decreases, Y increases.3.3. If r = 0, the variable are said to be uncorrelated.3.4. The p-value of a correlation coefficient depends only on the magnitude of

r and the sample size n 4. Regression analysis – A statistical tool that utilizes the relation between two or

more quantitative variables so that one variable can be predicted from the other.b. For categorical variables:

1. Simple group comparisons2. Odds ratio, relative risk, and rate ratio3. Logistic regression models

c. For continuous variables:1. Correction coefficient 2. Regression coefficient3. Partial correlation coefficients and multivariate models

34

Study Validity1. Internal Validity2. External Validity

Study Bias1. Selection bias2. Information bias3. Confounding

Definition of Confounding（干擾作用）a. The effect of an extraneous variable that wholly or partially accounts for the apparent

effect of the study exposure. (暴露因子對研究結果之影響，全部或部分其實來自某 外來因素 )

b. Confounder （干擾因素）is a third variable which may artificially create or mask an association between exposure and disease.（干擾因素為暴露因子與疾病狀態外之第三因素，而此干擾因素會促成或遮掩暴露因子與疾病狀態之相關聯）

Requirements for confounders:a. The confounder must be associated with the exposure (須與暴露相關)b. The confounder cannot be a consequence (pathway) f the exposure (不能是暴露之中間產物)

c. The confounder must be a risk factor for the disease (必須為一危險因子)

Confounder

Association Cause

Exposure Cause Disease(risk factor) (outcome)

35

Methods for controlling confoundinga. Study design

1. Eliminate the factor – limit the study group (obtain homogeneity in the sample)2. Randomization – Attempting to insure that each group will be equally

represented with confounding variables (make sure to check after randomization)3. Matching – Force the proper distribution of confounders into groups

b. Analysis of previous collected data1. Stratification/Analysis of subgroups

1.1. Compare exposed and unexposed groups within narrow ranges of the confounder

1.2. Decreases variability from the confounder2. Standardization

2.1. Indirect standardization 2.1.1. Use a standard population to give an expected number of cases by age

and (sometimes) gender2.1.2. Then calculate the observed cases in the sample2.1.3. Generate a standardized mortality ratio O/E which is independent of

age differences2.2. Direct standardization: Use a standard population to calculate an age-

adjusted rate. Look at percent of population by age categories and multiply by the rate of disease in each one. An age adjusted number can be calculated.

3. Modeling/Multivariate analyses: Use of a regression model to look at effects of numerous variables (exposure and confounders) on a disease. The independent effect of exposure can be sorted out.

36

Unit 12. Study Critique 1. Full reference

Does title reflect content?Is the abstract sufficient to get a general idea of background, purpose, methods, results, and conclusion?

2. Introduction a. Review of the literature

1. Appropriateness/relevance2. Completeness

b. Rationale 1. Is the rationale clear from the introduction?

c. Hypothesis/objective 1. Clarity2. Logical association with literature review and rationale

3. Study design and methods a. Design (overall objectives, level of measurement, specific design)

1. What are they trying to achieve?2. Ecological versus individual level of measurement

b. Population at risk1. Target population to which the results should apply

c. Sampling method, sample size, selection/exclusion criteria for study group and comparison group

1. What is the study (source) population?2. Clarity and appropriateness of sampling method3. Sufficiency of sample size4. Appropriateness and comparability of criteria applied to

groupsd. Data sources

1. Appropriateness of data/ ability to reach objectives2. Limitations of data

e. Ethical approval1. Were appropriate standards followed, how well is this

documented?f. Consent

1. What kind of consent is appropriate?2. What kind of consent was obtained (from whom, how)?

g. Dependent variable1. What are the outcomes under study?2. How are they defined and measured?

h. Independent variable(s)1. What are the predictors, risk factors under study?2. Wow are they defined and measured?

i. Confounders and effect modifiers1. What are the potential or known confounders or effect

modifiers?2. How are they defined and measured?3. How are they dealt with in study design and analysis?

j. Information bias controlled by study design

37

1. What are the strengths and limitations of the study design regarding to information bias (how are data collected, who provides the data, training or blinding methods etc.)

k. Selection bias controlled by study design1. What are the strengths and limitations of the study design

regarding to selection bias?2. How well are the selection methods designed to capture a

representative sample of the target population?3. What specific measures were taken to maximize participation

among those selected for inclusion?l. Is methodology appropriate and used correctly?m. Are methods described in sufficient detail to repeat the work (data

collection, preparation and analysis)?4. Results

a. Missing data1. What is the extent and distribution of missing data?2. How are missing data prevented?3. How are missing data dealt with?

b. Major findings1. What are the major findings (only own results should be

represented, results from other research should be in the discussion.)

2. How well do they relate to stated objectives3. How well do they relate to the methods described

c. Control for confounding1. How well was confounding controlled in design and analysis2. Is there likely to be residual confounding

d. Is the use of text and graphs to represent results appropriate? e. Are numeric results handled appropriately?

5. Discussion and conclusion a. Internal validity

1. Are the results likely to be valid (“true”) for the study population (have explanations other than causal association been ruled out, i.e. chance occurrence and confounding)

b. External validity 1. Given that the results are internally valid – are they likely to be

externally valid for other populations? Can the results be generalized? To what populations?

c. Consistency with other studies 1. Are the results and conclusions consistent with other studies?2. If not – what are the likely explanations for the inconsistency?3. Does the inconsistency diminish the value of the results or

conclusions?d. Do you agree with the conclusion reached by the authors? e. Are the authors conclusions clearly demarcated from those of others? f. Are there any “negative” findings that the authors have ignored in their

interpretation?

38

g. Is the work of others adequately considered and synthesized into the current work?

h. To what extent do the data support the conclusions made? To what extent is “guesswork” involved?

i. Theoretical importance 1. What is the theoretical importance of the study findings? To

what extent does the study contribute to our theoretical knowledge of the issue?

j. Practical importance 1. To what extent does the study contribute to our practical

knowledge of the issue?2. Should we do something differently in light of the study?

k. Further study 1. What are the “missing data” in the field of study?2. What guidance does the study provide in terms of areas for

further study?6. References and Other comments

a. How complete is the list of references? b. Is important references/knowledge missing? c. Are statements included without being supported by references? d. Are any references superfluous/unnecessary?

39