Research methodology - Clinical Tree

Essentials

1.
Research projects should be designed and undertaken in a structured, predetermined fashion.
2.
During the study design phase, assistance from a statistician is highly recommended.
3.
The study protocol should be written in advance of data collection and adhered to throughout the project.
4.
Most research mistakes relate to inadequate sample size calculations and selection bias in subject recruitment.
5.
Research ethics issues are becoming more important, especially since the introduction of new privacy legislation. Ethics committee authorization must be sought prior to study commencement.

Introduction

One important strategy in clinical research is to compare groups of human subjects. These might be different groups or the same group preintervention and postintervention. The methods used are mainly nonexperimental (i.e. observational). They are based on what we can observe and compare in groups of people within populations. By comparing the characteristics (such as behaviours and exposures) and the health experiences of these groups of people, it is possible to identify associations that might be responsible for the cause of a disease.

Initiating the research project

Research question

The research question forms the basis of every research study and is the reason that it is undertaken. It is the scientific, clinical, practical or hypothetical question that, when answered, will allow the researcher to apply newly found knowledge for some useful purpose.

The research question may be generated from many sources, including questions raised by clinical observations, the published medical literature, scientific conferences, seminars and discussions or the effectiveness of currently used or new treatment.

For example:

Is drug A better than drug B?

Study hypothesis

A hypothesis is a bold statement of what we think the answer to the research question is. Essentially, it is our best guess of what the underlying reality is. As such, it has a pivotal role in any study. The purpose of a research study is to weigh the evidence for and against the study hypothesis. Accordingly, the hypothesis is directly related to the research question.

For example:

‘directional’ hypothesis: drug A is better than drug B
‘null’ hypothesis: drug A is as good as drug B.

In expressing a hypothesis, the researcher needs to be very specific about who or what is to be observed and under what conditions. A failure to define clearly the study groups and the study end points often leads to sloppy research.

Study aims

The aims of a study are a description of what the researcher hopes to do in order to weigh up the evidence for and against the study hypothesis.

For example:

This study aims to determine which is the better drug, drug A or drug B.

Assembling the research team

Most research projects are undertaken as collaborative efforts with the co-investigators each contributing in their area of expertise. Co-investigators should meet the criteria for co-authorship of the publication reporting the study’s findings.

Usually, the person who has developed the research question takes the role of principal investigator (team leader) for the project. Among the first tasks is to assemble the research team. Ideally, the principal investigator determines the areas of expertise required for successful completion of the project (e.g. biostatistics) and invites appropriately skilled personnel to join the team. It is advisable to keep the numbers within the team to a minimum. In most cases, three or four people are adequate to provide a range of expertise without the team becoming cumbersome. It is recommended that nursing staff be invited to join the team, if this is appropriate. This may foster research interest among these staff, improve departmental morale and greatly assist patient enrolment and data collection.

All coinvestigators are expected to contribute time and effort to the project, although the extent of this contribution will vary. The temptation to include very senior staff or department heads simply to bolster the profile of the project should be avoided.

The importance of good communication within the research team cannot be overemphasized. This is usually the responsibility of the principal investigator and may involve regular meetings or reports. At the risk of flooding each coinvestigator with excessive or trivial communications (e.g. e-mail), selected important communications should be forwarded as they appear, for instance, notification of ethics committee approval and updates on enrolment.

Development of the study protocol

The protocol is the blue print or recipe of a research study. It is a document drawn up prior to commencement of data collection that is a complete description of the study to be undertaken. Every member of the study team should be in possession of an up-to-date copy. Furthermore, an outside researcher should be able to pick up the protocol and successfully undertake the study without additional instruction. Care should be taken to appropriately number and track every version of the protocol.

Purpose of the study protocol

Research protocols are required:

for the ethics committee application
for applications for research funding
to facilitate the smooth and efficient running of the study through the provision of well-researched and documented information
for the basis of the Introduction and Methods sections of the final research report.

Protocol structure

The protocol should be structured largely in the style of a journal article’s Introduction and Methods sections. Hence the general structure is as follows:

Introduction

Background, including a brief summary of the literature.
Research question.
Hypothesis.
Aims.
Need for the proposed research (i.e. the purpose of the study).

Methods

Study design—a simple description of the design of the proposed study (e.g. randomized clinical trial, cohort study, cross-sectional survey).
Study setting and period—a description of where and when the study will take place.
Study subjects—inclusion and exclusion criteria and a description of how participants are to be recruited.
Procedures and interventions—the nature of any interventions to be used, including information on safety, necessary precautions and rationale for the choice of dose(s).
Study end points (outcome variables)—variables that are impacted upon by the factors under investigation (e.g. those that are affected by a study intervention).
Data collection instruments (e.g. questionnaires, proformas, equipment).
Data collection procedures including quality-control procedures to ensure integrity of data.
Data management—including a description of how data will be handled, how privacy concerns will be addressed and how storage and backup of data will be undertaken.
Bias and confounding control—sources of bias and variability and measures to be taken to address them.
Ethical issues—subject confidentiality, safety, security and access to data.
Statistical analysis:
- sample size: a description of calculations used to determine sample size and assumptions included in this process should be included. This should include calculations, where appropriate, to ensure that it is clear that the study can recruit a sufficient number of patients to answer the research question
- data analysis: this should include a description of the primary variables to be analysed, a specification of any a priori subgroup analyses and the statistical methods to be used. It is highly recommended that a statistician be consulted during protocol development and for data analysis.

This general plan should be followed in the preparation of any study protocol. However, the final protocol will vary from study to study.

Study design

Study design, in its broadest sense, is the method used to obtain data to weigh up the evidence for and against the study hypothesis. Many factors influence the decision to use a particular study design and each design has advantages and disadvantages. For a more extensive discussion on study design the reader is referred elsewhere.

Observational studies

In general, research studies examine the relationship between an exposure or risk factor (e.g. smoking, obesity, vaccination) and an outcome of interest (e.g. lung cancer, cardiac disease, protection from infection).

In observational (non-experimental) studies, the principal challenge is to find a naturally occurring experiment (i.e. a comparison of two or more populations that enables the investigator to address a hypothesis about the outcome of interest).

Cross-sectional studies

Cross-sectional studies examine the present association between two variables. For example, within a population you could take a single random sample of all persons, measure some variable of interest (e.g. lung function) and then correlate that variable with the presence or absence of lung cancer. Data are often collected in surveys and the information on exposure and outcome of interest is collected from each subject at one point in time. The main outcome measure obtained from a cross-sectional study is prevalence.

Ecological studies

Ecological studies relate the rate of an outcome of interest to an average level of exposure that is presumed to apply to all persons in the population or group under investigation. So, for example, we could determine the association between the average amount smoked per capita in different countries and the incidence of lung cancer in each country.

Cohort studies

In a cohort study, a group of individuals in whom the personal exposures to a risk factor have been documented are followed over time. The rate of disease that subsequently occurs is examined in relation to the individuals’ exposure levels. For example, within a population you could take a sample (cohort) of healthy individuals, document their personal past and ongoing smoking history and relate that to the subsequent occurrence of lung cancer in that same sample. Although not as powerful a study design as clinical trials (see later), cohort studies are able to provide valuable data relating to the causation of disease.

Case-control studies

Case-control studies are retrospective analyses that involve a comparison between a representative sample of subjects with an outcome of interest (cases) and another sample of people without the outcome (controls). If an antecedent feature (exposure) is found to be more common in the cases than the controls, this suggests an association between that exposure and the development of the outcome. The frequencies of past exposures to risk factors of interest are compared in each group. Case-control studies provide only medium-level evidence of an association between exposure and outcome of interest.

Case reports and case series

This study design is often employed in emergency medicine research. The clinical details (history, management, outcome) of interesting or similar patients are described. This study design provides weak evidence for an association between exposure and outcome of interest and is best employed for hypothesis generation. For example, a series of patients who all developed skin necrosis after being bitten by a certain spider would reasonably lead to the hypothesis that the venom of the spider of interest contained a particular tissue necrosis factor. However, this hypothesis would need to be proven by the isolation of the factor and experimental demonstration of its effects.

Data for case reports/series are often extracted from medical record reviews or existing databases. This is one reason for the weakness of this study design insofar as the data were most likely collected for purposes other than the research study. Accordingly, such data are often of low quality and may suffer from inaccuracies, incompleteness and measurement bias.

Experimental or interventional studies

In an experimental study, the researcher is more than a mere observer and actively manipulates the exposure of study subjects to an exposure of interest (risk) and measures the effects (outcomes) of this manipulation.

The preferred form of experimental study is currently the randomized controlled trial, in which the intervention is randomly assigned at the level of the individual study subject. Although this is the most scientifically rigorous design, other study designs must often be used for a number of reasons including:

the state of knowledge about a disease process
real-world opportunities
logistics and costs
ethical considerations.

For ethical reasons, we cannot easily use experimental studies to study factors that are thought to increase the risk of disease in humans. For example, you could not do a study where you ask half of the group to smoke for 10 years and half of the group to remain non-smokers.

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