Acknowledgment: EPIET/EUPHEM Choice of reference group for comparison Tunis, 29th October 2014 Acknowledgment: EPIET/EUPHEM Dr Adela Paez MediPIET Scientific Coordinator – ECDC, Sweden adela.paezjimenez@ecdc.europa.eu

Learning objectives Source population How to choose your comparison group: What is a good control?

Epidemiologists .... compare occurrence of outcome depending on presence or absence of exposure disease incidence in different time-periods in a population First, we need to understand what is the source population!

Cases Controls Source population Exposed Sample Unexposed The source population is the source of the cases The control group is the sample of the source population representative with regard to exposure Controls

The control group “The comparison group serves to provide an estimate of the exposure distribution in the source population from which the cases originate.” Rothman KJ, 1986

Control characteristics If controls represent source population, they need to: be representative of exposures in source population be identified as cases if they had disease under study have same exclusion and restriction criteria as cases

Example of an outbreak 32 cases of Salmonella Enteritidis Granada, Spain (population 230,000) onset through September 2014 age range 15 – 48 years 19 male, 13 female Not belonging to a defined group such as attendants of a common event, etc. No recent travel abroad What type of study would you conduct? What is the source population?

Source population Residents of Granada aged above 14 years during September 2014 who have not recently travelled abroad

Source population Residents of Granada aged above 14 years during September 2014 who have not recently travelled abroad Controls should then be representative of this population

Case definition Resident of Granada aged above 14 years with isolate of Salmonella Enteritidis in faecal sample during September 2014 Exclusion: Travel abroad in week before illness

How to select controls? Aim for random sample of source population Not always feasible

Selecting controls (examples) Population / community General practitioners Neighbourhood Friends or acquaintances Hospital

Population / community controls Is there a list or register of source population? Such a list should be complete contain all cases be readily accessible identify specified characteristics, e.g. age Take random sample

or... random digit dialling using residential directories or mobile numbers quick and easy but may be biased in selection telephone ownership availability geographical area participation

Population / community controls Advantages Best choice if the source population = community Good representation of the source population Cost and time efficient Disadvantages Possible only in countries where population register exist Depends on the completeness of register

General practitioners Advantages well defined catchment population easily accessible cost and time efficient Disadvantages underrepresentation of mobile population underrepresentation of private care users possible only in countries where GP registration required by law

Neighbourhood controls Advantages no need for population register similar socio-economic status and environmental exposure Disadvantages might be too similar to cases low co-operation may be time consuming, expensive

Friends / family controls Advantages Good matching for social and genetic factors Can be quick and easy People motivated to participate Disadvantages Effectively link the cases and controls May not be able to detect a difference in exposure of importance

Hospital controls Advantages Disadvantages useful if all cases identified from hospital register easy to identify cost and time efficient Disadvantages different catchments for different diseases may not be representative of source population overmatching on exposures for other diseases

Controls may not be easy to find Representative of exposure Exposure should not be a criteria for selecting

Example of an outbreak 32 cases of Salmonella Enteritidis Granada, Spain (population 230,000) onset through September 2014 age range 15 – 48 years 19 male, 13 female no recent travel abroad

Source population Residents of North Yorkshire aged above 14 years during April 2012 who have not recently travelled abroad Controls should then be representative of this population

Which reference group ? How would you select controls ? (2 minutes!) You are in charge of the case control study! How would you select controls ? No population register or list is available Please discuss with a person next to you (2 minutes!)

Some common questions Immune populations 100% ill Non-cases as controls

1. Immune subjects Difficult to identify their immune status May have been cases in the past Not part of the source population May introduce bias and under-estimation of effect OR towards 1

2. Which control group if 100% ill ? What if close to 100% of population ill? Try to have severity Cases: severe cases Control group: less severe cases

Outbreak of S. Enteritidis in a Kebab restaurant, North East London February 2005 Food specific attack rates of severe case (AR), relatives risks (RR), 95% confidence intervals (95% CI) amongst cases. Food eaten Food not eaten Severe Total AR% RR 95% CI Salad 10 12 83.3 32 71 45.1 1.9 1.3-2.7 Chips 11 14 78.5 31 69 44.9 1.8 1.2-2.6 Sauce 59 52.5 24 45.8 1.2 0.7-1.9 57 54.4 26 42.3 1.3 0.8-2.1 Source: Giraudon I et al, EPIET, London HPA

Low attack rate: non-cases likely to represent exposure in source pop 3. Non-cases as controls Cases Low attack rate: non-cases likely to represent exposure in source pop Non- cases Source population start end High attack rate: non-cases unlikely to represent exposure in source population Cases Source population Non- cases start end

Outbreak of food borne disease in a nursing home Outbreak of food borne disease in a nursing home. 100 residents, 40 cases Cohort Source Population Non cases Cases ARe = 60% ARu = 10% RR = 6 E 36 24 60 E 4 36 40

Outbreak of food borne disease in a nursing home Outbreak of food borne disease in a nursing home. 100 residents, 40 cases Cohort Potential control groups Sample Non cases Source Population Non cases Cases E 36 24 60 12 E 4 36 40 18 RR = 6 OR = 13.5

Outbreak of food borne disease in a nursing home. 100 residents, 40 cases Cohort Potential control groups Sample Source Population Source Population Sample Non cases Non cases Cases E 36 24 60 12 30 4 36 40 18 20 E RR = 6 OR = 13.5 OR = 6

To sum up…

Key points in choosing controls Define source population Think of the cohort you could have done Aim for representative sample Review pros and cons of available options

Characteristics of good controls Come from the same population as the cases Have the same opportunity of exposure as cases Could be recruited as cases if diseased Have exposure window identical to cases

Dealing with imperfect control groups Examine the limitations of your control group with respect to each criteria Assess in which way the limitation will affect the odds ratio Interpret your results in light of this review

Conclusions No control group is perfect Consider the advantages and disadvantages of the available options Aim to minimise error within constraints of resources and urgency of study

Be prepared to defend your choice…

Research question (1/2) 12% Hepatitis C Virus (HCV) prevalence in Egypt How would you identify current risk factors for HCV infection? What type of study would you conduct? Hint: we need to identify new HCV infections Difficulty: the majority (80%) of acute HCV infections are asymptomatic The highest HCV prevalence in the world occurs in Egypt at an estimated 12% [1], i.e. 10 to 20 fold higher than in Northern Europe [2] or in the United States [3]. The bulk of chronic infection is age-related [4] and occurs among persons of rural origin. Cohort studies have estimated a 9% prevalence and 0.8/ 1000 person-years incidence in Upper Egypt, and a 24% prevalence and 6.8/1000 incidence in the Nile Delta [5,6]. The widespread schistosomiasis treatment campaigns with intravenous tartar emetic, carried out in the countryside in the 60’s- early 80’s, ignited this epidemic through reuse of insufficiently sterilised needles and syringes [7]. Since then, cross-sectional studies have shown unsafe injection practices, history of blood transfusion, invasive medical procedures, and instrument-assisted birth deliveries as associated with HCV infection [8–10]. Intra-familial transmission may also have played an important role, as evidenced in two recent cohort studies

Research question (1/2) Provided you conduct a case-control study with acute symptomatic hepatitis C patients identified at the Fever Hospitals in Cairo, How would you select controls? The highest HCV prevalence in the world occurs in Egypt at an estimated 12% [1], i.e. 10 to 20 fold higher than in Northern Europe [2] or in the United States [3]. The bulk of chronic infection is age-related [4] and occurs among persons of rural origin. Cohort studies have estimated a 9% prevalence and 0.8/ 1000 person-years incidence in Upper Egypt, and a 24% prevalence and 6.8/1000 incidence in the Nile Delta [5,6]. The widespread schistosomiasis treatment campaigns with intravenous tartar emetic, carried out in the countryside in the 60’s- early 80’s, ignited this epidemic through reuse of insufficiently sterilised needles and syringes [7]. Since then, cross-sectional studies have shown unsafe injection practices, history of blood transfusion, invasive medical procedures, and instrument-assisted birth deliveries as associated with HCV infection [8–10]. Intra-familial transmission may also have played an important role, as evidenced in two recent cohort studies

MediPIET Scientific Coordinator Thank you! Dr Adela Paez MediPIET Scientific Coordinator adela.paezjimenez@ecdc.europa.eu

References Rothmann KJ, Greenland S. Modern epidemiology. Lippincott-Raven 1998. Hennekens CH, Epidemiology in Medicine. Lippincott-Williams and Wilkins 1987.

Investigation 2 Neonatal ward of hospital X 30 cases of Klebsiella pneumoniae (2 deaths) The hospital epidemiologist wants to identify potential risk factors How would you select controls?

Investigation 3 250 cases of tick-borne encephalitis (TBE) reported anually in two regions (population: 8 milion) of country X 10% of infected develop disease Infection and vaccination lead to long-lasting immunity Risk factors not well established Contact with ticks (occupational and recreational outdoor activities) How would you select controls to identify risk factors?

Investigation 4 In January 2014, the Public Health Agency of Sweden observed a nationwide increase in notified listeriosis cases between October 2013 and March 2014. Isolates from 32 cases had identical Pulsed Field Gel Electrophoresis (PFGE) patterns, suggesting a common source. The median age of cases was 77 years and 23 (72%) were female. It’s now June 2014. How would you select the controls? What questions would you ask?

What if: Only non-cases as controls? If attack rate is low, non-cases likely to represent exposures in source population can use them as controls If attack rate is high, non-cases unlikely to represent exposure in source population OR may be over-estimated More accurate not to exclude cases from control group Concept of case-cohort studies!

Case-cohort design Aim of control group: properly reflect the exposure in the source population Source pop originally includes people who will later can develop the disease Controls selected from all individuals at risk at the start of the study sampled regardless whether or not they will fall ill No need to document disease status among controls OR estimates relative risk