Integrated Medical Education Resources: 150201L

Lecture to female medical students on February 1 and 8, 2015 by Professor Omar Hasan Kasule Sr., MB ChB (MUK), MPH (Harvard), DrPH (Harvard)

AIM

Critically appraise articles regarding causality
Interpret results of articles

SPECIFIC OBJECTIVES

Understand the different types of studies
Interpret measures of disease
Understand and apply criteria of causality

CONCEPTS OF DISEASE CAUSATION

The concept of the causal triangle (environment, host, and disease) has been used for many years to simplify epidemiological reasoning.
Disease risk is a probability.
A risk factor is known empirically to be involved in disease causation.
Risk indicators are likely to be causes but are not yet confirmed.
Data on causes can be obtained from animal or human experiments/observations.

TYPES OF CAUSES 1

Causes may be defined as causative or preventive.
A risk factor is described as sufficient when its mere presence will trigger the disease concerned. In practice a sufficient cause refers to a constellation of 2 or more risk factors since most diseases are multi-causal.
One disease normally has more than 1 sufficient cause.
There are some risk factors that are always present in all sufficient causes of the disease. These are referred to as necessary causes.

TYPES OF CAUSES 2

Causes may be weak or strong.
Causes may interact either cooperatively in disease causation (synergy) or act against one another (antagonism).
The causal chain or causal pathway is multi-stage. It is initiated by the main risk factor. The final stages are due to promotors.

CAUSALITY

Association of disease with a putative risk factor may be statistically or non-statistical.
Statistical association can be causal or non-causal.
One disease may have 2 or more co-factors.
One disease may have 2 quite different independent causes. One cause leads to 2 different diseases.

ESSENTIAL CRITERIA OF CAUSALITY

Specificity,
Strength,
Time sequence,
Biological plausibility

BACK UP CRITERIA

Dose-effect relationship
Repetition
Consistency
Evidence from intervention
Experimental evidence.

TYPES OF STUDIES

Observational: cross sectional, case control, and follow up (cohort)

o Cross sectional: observe ‘exposure=risk factor’ and ‘disease’ at the same time and create a 2x2 table

o Case control: compare ‘cases’ of disease with normal ‘controls’ regarding ‘exposure’

o Select 2 groups ‘exposed’ to the risk factor and ‘not exposed’ to the risk factor and follow over many years to compare occurrence of disease in both groups

Experimental: randomized clinical trials and randomized community trials

CRITICAL APPRAISAL OF A JOURNAL ARTICLE 1: COMMON PROBLEMS

For critical reading of scientific literature, the reader must be equipped with tools to be able to analyze their methodology and data analysis critically before accepting their conclusions.
Common problems in published studies are incomplete documentation, design deficiencies, improper significance testing and interpretation.

CRITICAL APPRAISAL OF A JOURNAL ARTICLE 2: TITLE, ABSTRACT, and INTRODUCTION

The main problem of the title is irrelevance to the body of the article.
Problems of the abstract are failure to show the focus of the study and to provide sufficient information to assess the study (design, analysis, and conclusions).
Problems of the introduction are failures of the following: stating the reason for the study, reviewing previous studies, indicating potential contribution of the present study, giving the background and historical perspective, stating the study population, and stating the study hypothesis.

CRITICAL APPRAISAL OF A JOURNAL ARTICLE 3:PROBLEMS OF STUDY DESIGN

going on a fishing expedition without a prior hypothesis, study design not appropriate for the hypothesis tested, lack of a comparison group, use of an inappropriate comparison group, selection of cases and controls from different populations, and sample size not big enough to answer the research questions.
Terms confusion: ‘Measurement’ is using instruments. ‘Calculation’ deals with numbers and formulas.

CRITICAL APPRAISAL OF A JOURNAL ARTICLE 4: PROBLEMS IN STUDY DESIGN

Terms confusion: ‘Estimation’ is used in two senses as an approximation in measurements or as computation of statistical parameters. ‘Determination’ is a general term for getting to a conclusion by use of the 4 methods above.
Terms confusion: The term ‘study’ is generic and can be confused with experiment that refers to only some types of studies.

CRITICAL APPRAISAL OF A JOURNAL ARTICLE 5: PROBLEMS OF DATA COLLECTION

missing data due to incomplete coverage,
loss of information due to censoring and loss to follow-up,
poor documentation of data collection,
methods of data collection inappropriate to the study design.

CRITICAL APPRAISAL OF A JOURNAL ARTICLE 6: PROBLEMS OF DATA ANALYSIS

Not stating type of hypothesis testing (p value or confidence interval), use of the wrong statistical tests, drawing inappropriate conclusions,
use of parametric tests for non-normal data, multiple comparisons or multiple significance testing, assessment of errors, assessment of normality of data,
using appropriate scales and tests, using the wrong statistical formula, and confusing continuous and discrete scales.

CRITICAL APPRAISAL OF A JOURNAL ARTICLE 7: PROBLEMS IN DATA REPORTING

selective reporting of favorable results, numerators without denominator, inappropriate denominators, numbers that do not add up, tables not labeled properly or completely,
numerical inconsistency (rounding, decimals, and units), stating results as mean +/- 2SD for non-normal data, stating p values as inequalities instead of the exact values, missing degrees of freedom and confidence limits.

CRITICAL APPRAISAL OF A JOURNAL ARTICLE 8: PROBLEMS IN THE CONCLUSION

repeating the results section, not discussion of the consistency of conclusions with the data and the hypothesis,
extrapolations beyond the data, not discussing short-comings and limitations of the study, not evaluation of statistical conclusions in view of testing errors,
non assessment of bias (misclassification, selection, and confounding), assessment of precision (lack of random error), and assessment of validity (lack of systematic error).

CRITICAL APPRAISAL OF A JOURNAL ARTICLE 9: VALIDITY

Internal validity is achieved when the study is internally consistent and the results and conclusions reflect the data.
External validity is generalizability (i.e. how far can the findings of the present study be applicable to other situations) and is achieved by several independent studies showing the same result.
Inability to detect the outcome of interest due to insufficient period of follow-up, inadequate sample size, and inadequate power.

MEASURES OF DISEASE OCCURRENCE

Incidence = how many cases of disease in 100,000 of population in 1 year
Prevalence= proportion of the population with the disease

MEASURES OF ASSOCIATION

For continuous data based on measurement: t test and p value
For categorical data based on counting: chi square test and op value
P <0.05 indicates significant association
P>0.05 indicates no significant association

MEASURES OF EXCESS DISEASE OR DISEASE RISK OR EFFECT)

Rate ratio = incidence of disease in exposed compared to incidence of disease in the non exposed
Rate difference = incidence of disease in the exposed – incidence of disease in the non exposed
Odds = p / 1-p where p=prevalence
Odds ratio = odds of disease in the exposed compared to odds of disease in the non exposed.

WHEN STATISTICAL RESULTS ARE NOT RELIABLE

Measurement bias = bias during data collection in favor of one outcome
Selection bias = selection of study subjects favoring one outcome
Confounding = confusion when the risk factor ‘hides’ behind another factor

ANALYSIS OF THE ARTICLE ON ASBESTOS 1

Alfonso HS et al. Effects of asbestos and smoking on the levels and rates of change of lung function in a crocidolite exposed cohort in Western Australia. Thorax. 2004 Dec;59(12):1052-6.
INTRODUCTION Increased rates of death from asbestos related diseases have been reported in former workers and residents exposed to crocidolite (blue asbestos) at Wittenoom, Western Australia. Exposure to asbestos is associated with reduced static lung volumes, gas transfer and lung compliance, and a restrictive ventilatory abnormality.
METHODS: The effects of crocidolite exposure and smoking history on levels and rates of change of lung function were evaluated using a linear mixed model. Lung function was measured as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC.

ANALYSIS OF THE ARTICLE ON ASBESTOS 2

RESULTS: Cumulative doses of asbestos and the presence of radiographic asbestosis were associated with lower levels of FEV1 and FVC and a steeper decline during the period of observation. Subjects exposed to asbestos at a younger age had lower levels of FEV1 and FVC. Current smokers had lower levels and a steeper decline in lung function than never smokers. No significant interactions between crocidolite exposure and smoking on the levels or rates of change of lung function were found.
CONCLUSIONS: The deleterious effects of crocidolite exposure on lung function persist in this population, despite asbestos exposure having ceased more than 30 years ago. No significant interactions were found in this population between asbestos and smoking at the first visit or longitudinally.

ANALYSIS OF THE ARTICLE ON ASBESTOS 3

Measures of disease occurrence
Measures of association
Measures of effect

ANALYSIS OF THE ARTICLE ON SLEEP APNOEA AND MORTALITY 1

Bliwise DL et al. Sleep apnea and mortality in an aged cohort. Am J Public Health. 1988 May;78(5):544-7.
In the aged, sleep may be a vulnerable period for death from cardiovascular causes. Because of its high prevalence in the elderly, sleep apnea has been suggested to be one mechanism contributing to such sleep-related mortality.
In this study, a cohort of 198 non-institutionalized elderly individuals (mean age at entry = 66) were followed for periods up to 12 years after initial polysomnography.

ANALYSIS OF THE ARTICLE ON SLEEP APNOEA AND MORTALITY 2

The mortality ratio for sleep apnea (defined as a Respiratory Disturbance Index of over 10 events per sleep hour) was estimated to be 2.7 (95% CI = .95, 7.47).
Multiple regression with the Cox proportional hazards model suggested that cardiovascular death was most clearly associated with age in this cohort.
These results raise the possibility that "natural" death during sleep in the elderly may be associated with specific pathophysiological events during sleep.

ANALYSIS OF THE ARTICLE ON SLEEP APNOEA AND MORTALITY 3

What type of study is this?
What measure of excess disease risk was used in this study?
Discuss causality using the criteria covered in the lecture

JAMA ARTICLE ON CRITICAL APPRAISAL

ANALYSIS OF DYKEN PAPER ON SLEEP APNOEA AND STROKE 1

Dyken ME et al,. Investigating the relationship between stroke and obstructive sleep apnea. Stroke. 1996 Mar;27(3):401-7.
BACKGROUND AND PURPOSE:We aimed to prospectively determine whether the incidence of obstructive sleep apnea in patients with recentstroke was significantly different from that of a sex- and age-matched control group with no major medical problems.
METHODS: We prospectively performed overnight polysomnography in 24 patients with a recent stroke (13 men and 11 women; mean age [+/- SD], 64.6 +/- 10.4 years) and 27 subjects without stroke (13 men and 14 women; mean age, 61.6 +/- 8.8 years). Patients with either ischemic or hemorrhagic stroke were entered into this study. Polysomnographic evaluations were performed within approximately 2 to 5 weeks after each patient'sstroke.

ANALYSIS OF DYKEN PAPER ON SLEEP APNOEA AND STROKE 2

RESULTS 1: Obstructive sleep apnea was found in 10 of 13 men with stroke (77%) and in only 3 of 13 male subjects without stroke (23%) (P=.0169). Seven of 11 women with stroke (64%) had obstructive sleep apnea, while only 2 of 14 female subjects without stroke (14%) had obstructive sleepapnea (P=.0168). For men with stroke, the mean apnea/hypopnea index (+/- SE) was 21.5 +/- 4.2 events per hour, while for male subjects withoutstroke it was 4.8 +/- 1.8 events per hour (P=.0014).
RESULTS 2: For women with stroke the mean apnea/hypopnea index was 31.6 +/- 8.8 events per hour, while for female subjects without stroke it was 2.9 +/- 1.6 events per hour (P=.0024). The 4-year mortality for patients with stroke was 20.8%. All patients with stroke who died had obstructive sleep apnea.

ANALYSIS OF DYKEN PAPER ON SLEEP APNOEA AND STROKE 3

CONCLUSIONS 1: Patients with stroke have an increased incidence of obstructive sleep apnea compared with normal sex- and age-matched control subjects.
CONCLUSIONS 1Hypoxia and hemodynamic responses to obstructive sleep apnea may have predisposed these patients to stroke.

ANALYSIS OF THE PALOMAKI PAPER ON APNOEA AND STROKE 1

Palomäki H et al. Snoring, sleep apnea syndrome, and stroke. Neurology. 1992 Jul;42(7 Suppl 6):75-81; discussion 82
Increasing evidence suggests that snoring and sleep apnea are associated with cerebrovascular diseases.
Several other factors may be involved in this association because many established or potential risk factors for stroke are related to snoring and sleep apnea. These include arterial hypertension, coronary heart disease, age, obesity, smoking, and alcohol consumption.
Recent epidemiologic and clinical studies indicate, however, that snoring can increase the risk of stroke independently of these confounding factors.

ANALYSIS OF THE PALOMAKI PAPER ON APNOEA AND STROKE 2

Accumulating epidemiologic evidence of long-term harmful effects of the obstructive sleep apnea syndrome appears to be related to increasing vascular morbidity and mortality.
Potential mediators among snoring, obstructive sleep apneas, and stroke include cardiac arrhythmias and other hemodynamic disturbances, increased levels of catecholamines, and disturbances in cerebral blood flow caused by sleep apneas, as well as hypoxemic periods that may potentiate atherosclerosis.

ANALYSIS OF THE ARTICLE ON SLEEP APNEA AND STROKE 1

Yaranov DM et al. Effect of obstructive sleep apnea on frequency of stroke in patients with atrial fibrillation. Am J Cardiol. 2015 Feb 15;115(4):461-5.
Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke that is not included in the usual cardioembolic risk assessments for patients with atrial fibrillation (AF).
The aim of this study was to investigate the impact of OSA on stroke rate in patients with AF.
Patients with AF and new diagnoses of OSA were identified from retrospective chart review. Those with histories of stroke at the time of the sleep study were excluded.
The primary outcome was the incidence of stroke, determined by a physician investigator blinded to the results of polysomnography.

ANALYSIS OF THE ARTICLE ON SLEEP APNEA AND STROKE 2

Among the study population, the occurrence of first-time stroke was 22.9%. Ischemic stroke was more common in patients with OSA compared with patients without (25.4% vs 8.2% respectively, p = 0.006).
After controlling for age, male gender, and coronary artery disease, the association between OSA and stroke remained statistically significant, with an adjusted odds ratio of 3.65 (95% confidence interval 1.252 to 10.623).
A positive dose effect of the apnea-hypopnea index on the rate of stroke was observed (p = 0.0045).

ANALYSIS OF THE ARTICLE ON SLEEP APNEA AND STROKE 3

What type of study is this?
What measure of excess disease risk was used in this study?
Discuss causality using the criteria covered in the lecture

150201L - CAUSALITY