12e. Statistical methods – sensitivity analyses

What to write

Describe any sensitivity analyses.

Explanation

Sensitivity analyses are useful to investigate whether or not the main results are consistent with those obtained with alternative analysis strategies or assumptions1. Issues that may be examined include the criteria for inclusion in analyses, the definitions of exposures or outcomes2, which confounding variables merit adjustment, the handling of missing data3,4, possible selection bias or bias from inaccurate or inconsistent measurement of exposure, disease and other variables, and specific analysis choices, such as the treatment of quantitative variables (see 11. Quantitative variables). Sophisticated methods are increasingly used to simultaneously model the influence of several biases or assumptions5–7.

In 1959 Cornfield et al. famously showed that a relative risk of 9 for cigarette smoking and lung cancer was extremely unlikely to be due to any conceivable confounder, since the confounder would need to be at least nine times as prevalent in smokers as in non-smokers8. This analysis did not rule out the possibility that such a factor was present, but it did identify the prevalence such a factor would need to have. The same approach was recently used to identify plausible confounding factors that could explain the association between childhood leukaemia and living near electric power lines9. More generally, sensitivity analyses can be used to identify the degree of confounding, selection bias, or information bias required to distort an association. One important, perhaps under recognised, use of sensitivity analysis is when a study shows little or no association between an exposure and an outcome and it is plausible that confounding or other biases toward the null are present.

Examples

“Because we had a relatively higher proportion of ‘missing’ dead patients with insufficient data (38/148=25.7%) as compared to live patients (15/437=3.4%) (…), it is possible that this might have biased the results. We have, therefore, carried out a sensitivity analysis. We have assumed that the proportion of women using oral contraceptives in the study group applies to the whole (19.1% for dead, and 11.4% for live patients), and then applied two extreme scenarios: either all the exposed missing patients used second generation pills or they all used third-generation pills”3.

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References

1.
Rothman KJgreenland s1998 basic methods for sensitivity analysis and external adjustment. In:rothman KJgreenland smodern epidemiology. 2nd ed lippincott raven 343 357.
2.
Custer B, Longstreth W, Phillips LE, Koepsell TD, Van Belle G. Hormonal exposures and the risk of intracranial meningioma in women: A population-based case-control study. BMC Cancer. 2006;6(1). doi:10.1186/1471-2407-6-152
3.
Dunn NR, Arscott A, Thorogood M. The relationship between use of oral contraceptives and myocardial infarction in young women with fatal outcome, compared to those who survive: Results from the MICA case-control study. Contraception. 2001;63(2):65-69. doi:10.1016/s0010-7824(01)00172-x
4.
Wakefield MA. Effect of restrictions on smoking at home, at school, and in public places on teenage smoking: Cross sectional study. BMJ. 2000;321(7257):333-337. doi:10.1136/bmj.321.7257.333
5.
Greenland S. The impact of prior distributions for uncontrolled confounding and response bias: A case study of the relation of wire codes and magnetic fields to childhood leukemia. Journal of the American Statistical Association. 2003;98(461):47-54. doi:10.1198/01621450338861905
6.
Lash TL, Fink AK. Semi-automated sensitivity analysis to assess systematic errors in observational data. Epidemiology. 2003;14(4):451-458. doi:10.1097/01.ede.0000071419.41011.cf
7.
Phillips CV. Quantifying and reporting uncertainty from systematic errors. Epidemiology. 2003;14(4):459-466. doi:10.1097/01.ede.0000072106.65262.ae
8.
Smoking and lung cancer: Recent evidence and a discussion of some questions. 1959;22.
9.
Factors that explain the power line configuration wiring code-childhood leukemia association: What would they look like? 2001;5.

Citation

For attribution, please cite this work as:
von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The STROBE reporting guideline for writing up observational studies in epidemiology. The EQUATOR Network guideline dissemination platform. doi:10.1234/equator/1010101

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Cohort studies

A cohort study is an observational study in which a group of people with a particular exposure (e.g. a putative risk factor or protective factor) and a group of people without this exposure are followed over time. The outcomes of the people in the exposed group are compared to the outcomes of the people in the unexposed group to see if the exposure is associated with particular outcomes (e.g. getting cancer or length of life).

Source.

Case-control studies

A case-control study is a research method used in healthcare to investigate potential risk factors for a specific disease. It involves comparing individuals who have been diagnosed with the disease (cases) to those who have not (controls). By analysing the differences between the two groups, researchers can identify factors that may contribute to the development of the disease.

An example would be when researchers conducted a case-control study examining whether exposure to diesel exhaust particles increases the risk of respiratory disease in underground miners. Cases included miners diagnosed with respiratory disease, while controls were miners without respiratory disease. Participants' past occupational exposures to diesel exhaust particles were evaluated to compare exposure rates between cases and controls.

Source.

Cross-sectional studies

A cross-sectional study (also sometimes called a "cross-sectional survey") serves as an observational tool, where researchers capture data from a cohort of participants at a singular point. This approach provides a 'snapshot'— a brief glimpse into the characteristics or outcomes prevalent within a designated population at that precise point in time. The primary aim here is not to track changes or developments over an extended period but to assess and quantify the current situation regarding specific variables or conditions. Such a methodology is instrumental in identifying patterns or correlations among various factors within the population, providing a basis for further, more detailed investigation.

Source

Systematic reviews

A systematic review is a comprehensive approach designed to identify, evaluate, and synthesise all available evidence relevant to a specific research question. In essence, it collects all possible studies related to a given topic and design, and reviews and analyses their results.

The process involves a highly sensitive search strategy to ensure that as much pertinent information as possible is gathered. Once collected, this evidence is often critically appraised to assess its quality and relevance, ensuring that conclusions drawn are based on robust data. Systematic reviews often involve defining inclusion and exclusion criteria, which help to focus the analysis on the most relevant studies, ultimately synthesising the findings into a coherent narrative or statistical synthesis. Some systematic reviews will include a meta-analysis.

Source

Systematic review protocols

TODO

Meta analyses of Observational Studies

TODO

Randomised Trials

A randomised controlled trial (RCT) is a trial in which participants are randomly assigned to one of two or more groups: the experimental group or groups receive the intervention or interventions being tested; the comparison group (control group) receive usual care or no treatment or a placebo. The groups are then followed up to see if there are any differences between the results. This helps in assessing the effectiveness of the intervention.

Source

Randomised Trial Protocols

TODO

Qualitative research

Research that aims to gather and analyse non-numerical (descriptive) data in order to gain an understanding of individuals' social reality, including understanding their attitudes, beliefs, and motivation. This type of research typically involves in-depth interviews, focus groups, or field observations in order to collect data that is rich in detail and context. Qualitative research is often used to explore complex phenomena or to gain insight into people's experiences and perspectives on a particular topic. It is particularly useful when researchers want to understand the meaning that people attach to their experiences or when they want to uncover the underlying reasons for people's behavior. Qualitative methods include ethnography, grounded theory, discourse analysis, and interpretative phenomenological analysis.

Source

Case Reports

TODO

Diagnostic Test Accuracy Studies

Diagnostic accuracy studies focus on estimating the ability of the test(s) to correctly identify subjects with a predefined target condition, or the condition of interest (sensitivity) as well as to clearly identify those without the condition (specificity).

Prediction Models

Prediction model research is used to test the accurarcy of a model or test in estimating an outcome value or risk. Most models estimate the probability of the presence of a particular health condition (diagnostic) or whether a particular outcome will occur in the future (prognostic). Prediction models are used to support clinical decision making, such as whether to refer patients for further testing, monitor disease deterioration or treatment effects, or initiate treatment or lifestyle changes. Examples of well known prediction models include EuroSCORE II for cardiac surgery, the Gail model for breast cancer, the Framingham risk score for cardiovascular disease, IMPACT for traumatic brain injury, and FRAX for osteoporotic and hip fractures.

Source

Animal Research

TODO

Quality Improvement in Healthcare

Quality improvement research is about finding out how to improve and make changes in the most effective way. It is about systematically and rigourously exploring "what works" to improve quality in healthcare and the best ways to measure and disseminate this to ensure positive change. Most quality improvement effectiveness research is conducted in hospital settings, is focused on multiple quality improvement interventions, and uses process measures as outcomes. There is a great deal of variation in the research designs used to examine quality improvement effectiveness.

Source

Economic Evaluations in Healthcare

TODO

Meta Analyses

A meta-analysis is a statistical technique that amalgamates data from multiple studies to yield a single estimate of the effect size. This approach enhances precision and offers a more comprehensive understanding by integrating quantitative findings. Central to a meta-analysis is the evaluation of heterogeneity, which examines variations in study outcomes to ensure that differences in populations, interventions, or methodologies do not skew results. Techniques such as meta-regression or subgroup analysis are frequently employed to explore how various factors might influence the outcomes. This method is particularly effective when aiming to quantify the effect size, odds ratio, or risk ratio, providing a clearer numerical estimate that can significantly inform clinical or policy decisions.

How Meta-analyses and Systematic Reviews Work Together

Systematic reviews and meta-analyses function together, each complementing the other to provide a more robust understanding of research evidence. A systematic review meticulously gathers and evaluates all pertinent studies, establishing a solid foundation of qualitative and quantitative data. Within this framework, if the collected data exhibit sufficient homogeneity, a meta-analysis can be performed. This statistical synthesis allows for the integration of quantitative results from individual studies, producing a unified estimate of effect size. Techniques such as meta-regression or subgroup analysis may further refine these findings, elucidating how different variables impact the overall outcome. By combining these methodologies, researchers can achieve both a comprehensive narrative synthesis and a precise quantitative measure, enhancing the reliability and applicability of their conclusions. This integrated approach ensures that the findings are not only well-rounded but also statistically robust, providing greater confidence in the evidence base.

Why Don't All Systematic Reviews Use a Meta-Analysis?

Systematic reviews do not always have meta-analyses, due to variations in the data. For a meta-analysis to be viable, the data from different studies must be sufficiently similar, or homogeneous, in terms of design, population, and interventions. When the data shows significant heterogeneity, meaning there are considerable differences among the studies, combining them could lead to skewed or misleading conclusions. Furthermore, the quality of the included studies is critical; if the studies are of low methodological quality, merging their results could obscure true effects rather than explain them.

Protocol

A plan or set of steps that defines how something will be done. Before carrying out a research study, for example, the research protocol sets out what question is to be answered and how information will be collected and analysed.

Source

Cohort_studies

In cohort studies, the investigators follow people over time. They obtain information about people and their exposures at baseline, let time pass, and then assess the occurrence of outcomes. Investigators commonly make contrasts between individuals who are exposed and not exposed or among groups of individuals with different categories of exposure. Investigators may assess several different outcomes, and examine exposure and outcome variables at multiple points during follow-up. Closed cohorts (for example birth cohorts) enrol a defined number of participants at study onset and follow them from that time forward, often at set intervals up to a fixed end date. In open cohorts the study population is dynamic - people enter and leave the population at different points in time (for example inhabitants of a town). Open cohorts change due to deaths, births, and migration, but the composition of the population with regard to variables such as age and gender may remain approximately constant, especially over a short period of time. In a closed cohort cumulative incidences (risks) and incidence rates can be estimated; when exposed and unexposed groups are compared, this leads to risk ratio or rate ratio estimates. Open cohorts estimate incidence rates and rate ratios.

Case_control_studies

In case-control studies, investigators compare exposures between people with a particular disease outcome (cases) and people without that outcome (controls). Investigators aim to collect cases and controls that are representative of an underlying cohort or a cross-section of a population. That population can be defined geographically, but also more loosely as the catchment area of health care facilities. The case sample may be 100% or a large fraction of available cases, while the control sample usually is only a small fraction of the people who do not have the pertinent outcome. Controls represent the cohort or population of people from which the cases arose. Investigators calculate the ratio of the odds of exposures to putative causes of the disease among cases and controls (see Item 16c). Depending on the sampling strategy for cases and controls and the nature of the population studied, the odds ratio obtained in a case-control study is interpreted as the risk ratio, rate ratio or (prevalence) odds ratio [@pmed-0040297-b016; @pmed-0040297-b017]. The majority of published case-control studies sample open cohorts and so allow direct estimations of rate ratios.

Cross-sectional_studies

In cross-sectional studies, investigators assess all individuals in a sample at the same point in time, often to examine the prevalence of exposures, risk factors or disease. Some cross-sectional studies are analytical and aim to quantify potential causal associations between exposures and disease. Such studies may be analysed like a cohort study by comparing disease prevalence between exposure groups. They may also be analysed like a case-control study by comparing the odds of exposure between groups with and without disease. A difficulty that can occur in any design but is particularly clear in cross-sectional studies is to establish that an exposure preceded the disease, although the time order of exposure and outcome may sometimes be clear. In a study in which the exposure variable is congenital or genetic, for example, we can be confident that the exposure preceded the disease, even if we are measuring both at the same time.