Bias in nephrological Studies : what it is and how to deal with it. Carmine Zoccali

1. Bias in nephrological Studies  : what it is and how to deal with it.  Carmine Zoccali

2. Clinical Research Valid Studies Systematic errors in the design or in the conduct of a study Bias: the tendency towards erroneous results

3. David Sackett 60 types of bias Selection Bias Information Bias Selection-Information Bias Publication Bias

4. Case Control Studies Cases Controls Exposed Unexposed The identification of cases and controls should be independent of the exposure status

5. Prospective Cohort Studies Exposed Group (test group)Exposure to Drugs Toxic substances…..Any purported risk factor for disease Diseased Non-diseased Exposed Unexposed Non exposed group (control group) Here it is important that we avoid a systematic error in the ascertainment of exposed and unexposed subjects

6. Odds Ratio = 4 Case Control Studies 10.000 subjects included in a study aimed at assessing the effect of past exposure to hydrocarbons and renal disease. Complete ascertainment in the reference population Cases Controls Exposed 500 1800 1 0.25 Odds of being exposed 7200 500 Unexposed 1000 9000

7. Odds Ratio = 4 Case Control Studies 10.000 subjects included in a study aimed at assessing the effect of past exposure to hydrocarbons and nephrotic syndrome. 50% cases and 10% of controls selected for the study Unbiased sampling, the identification of cases is independent of exposure status Cases Controls Exposed 250 180 Odds of being exposed 1 0.25 720 250 Unexposed 9000 900 1000 500

8. Odds Ratio = 6 Case Control Studies biased sampling, even though the investigator was unaware of this, the identification of cases was facilitated by knowledge of the exposure status by general practitioners that helped the enrollment of cases into this study This differential bias distorts the magnitude of the association between hydrocarbon exposure and nephrotic syndrome Cases Controls 300 250 Exposed 180 050 0.50 060 0.40 Odds of being exposed 1.5 0.25 720 250 200 Unexposed 500 900

9. David Sackett 60 types of bias Selection Bias Information Bias Selection-Information Bias Publication Bias

10. INFORMATION BIAS :Imperfect definitions of study variables or flawed data collection Exposure identification bias Recall bias Nephrotic syndrome & Hydrocarbon exposure Cases Controls Remedies Verification of the exposure information (i.e. checking names of all persons who worked or lived in proximity of plants processing hydrocarbons) Outcome identification bias Controls selected from a group of symptomatic subjects, e.g. patients referred to the same renal clinic and that turned out to be unaffected by renal disease Objective markers of hydrocarbon exposure: e.g.measure hydrocarbon metabolites in biological samples.

11. INFORMATION BIAS :Imperfect definitions of study variables or flawed data collection Exposure identification bias Interviewer bias Nephrotic syndrome & Hydrocarbon exposure A biased interviewer may help reminding past exposures with secondary questions more intensively in cases than in controls Remedies Standardising very carefully the interview : identical questionnaire in cases and controls Blinding the interviewer to the case-control status

12. Hypertensive ESRD INFORMATION BIAS :Imperfect definitions of study variables or flawed data collection Exposure identification bias Observer bias knowledge of the exposure status may affect the decision as to whether the outcome is present! Remedies Blinding the assessor to exposure status Diagnosis labeled as “possible”, “probable” “definite”. Suspect bias if differences emerge in the “possible” category only. Perneger TV Am J Epidem. 995; 141: 10-15 Multiple assessors Outcome identification bias Clinical History Diagnosis of hypertensive ESRD more likely !

13. Cases Controls Exposed Unexposed 30% misclassified Odds Ratio Odds Ratio = 3.4 = 4 INFORMATION BIAS :Imperfect definitions of study variables or flawed data collection Non Differential Misclassification ! Differential An example in Case-Control studies …the same applies to Cohort studies when the misclassification of exposure is independent of Case-Control status, i.e. the same in cases and controls 50 20 35 14 30% misclassified 0.54 0.16 0.25 1 65 50 80 86 Non differential misclassification weakens true associations !

14. Cases Controls Exposed Unexposed No misclassification Odds Ratio Odds Ratio = 6.2 = 4 INFORMATION BIAS :Imperfect definitions of study variables or flawed data collection Non Differential Misclassification ! Differential when the misclassification of exposure differs between Cases and Controls 50 14 30% misclassified 1 0.16 50 86 Had exposure misclassification occurred in cases but not in controls the Odds Ratio would have been weakened rather than increased! Differential misclassification may both increase or decrease true associations !

15. David Sackett 60 types of bias Selection Bias Information Bias Selection-Information Bias Publication Bias

16. Prevalence of Disease X estimated at time t: 4:24= 0.16 Incidence-Prevalence Bias Cohort study to establish the risk of disease X 24 Incident Risk: 8:24= 0.33 Prevalence gives a biased estimate of incident risk because severe cases may die early. Time 0 . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . t Remedy: Whenever possible estimate risk as incident risk. Survey

17. Cohort study Time 0 . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . ……. t a bias deriving from the fact that we apply to selected patient different criteria (information) for assessing the efficacy of screening or early detection programs Lead Time Bias Diagnosis (symptomatic phase) Death Lead Time ! Early diagnosis useful ? Death Early diagnosis (pre-clinical stage) Remedy If we are going to assess the usefulness of screening programs by survival analysis we should take into proper account the “lead time” and adjust the analysis accordingly.

18. David Sackett 60 types of bias Selection Bias Information Bias Selection-Information Bias Publication Bias

19. Publication Bias Is a bias generated in the selection process of the information that eventually gets publication Studies of the effect of drugs on important outcomes like renal disease progression are done by various research groups worlwide. GFR In 2001 Kasiske & co collated 13 studies on lipid lowering and renal outcomes in patients with CKD.

20. Journal editors might have been biased in accepting for publication positive studies. Alternatively authors of negative studies might have not submitted them because of the low probability for the study be accepted… How can we detect and prevent publication bias?

21. Outcome measure Funnel Plot better 0 10 100 1000 Sample size worse The outcome tends to be neutral (no effect) as the study size is larger: Publication bias likely. The outcome is independent of study size : Publication bias unlikely.

22. S & C Bias is the tendency to produce erroneous results Proper selection of cases and controls and of exposed and unexposed subjects is fundamental if we are to avoid bias Recall bias, Interviewer bias and observer bias all produce wrong information and misclassification of study subjects. Non differential misclassification weakens the strenght of a true association while non differential misclassification may either inflate or weaken the strength of a given association Prevalence may give a biased estimate of risk. Whenever possible risk should be estimated in cohort studies rather than in surveys. The time that leads the disease from the pre-clinical phase to the symptomatic phase should be carefully considered when assessing the usefulness of early detection programs. Be aware of publication bias.