INTRODUCTION
Health research is important to understand the epidemiology, etiology, risk and protective factors, clinical presentation, prognosis, and treatment of various health related conditions. Research also helps in knowing the changing trends in prevalence, clinical presentation, treatment, outcome, complications and a number of other related issues in various health conditions. Research also aims to assess new treatments and bring innovations in management of various illnesses. The research findings are also important for policy makers to allocate and prioritize resources for various health-related disciplines and conditions.
PLANNING RESEARCH
Research has to be done as per a preplanned strategy. It has to be guided by a set of rules or action plan. In the first place, a set of ideas for a research are to be identified or proposed.
On which areas should one do research? This depends on multiple factors. The reasons for doing research may vary from educating parts of the brain seldom exercised (probability of success = 0.9) to winning the Nobel Prize (probability of success ≤ 0.000001). It depends upon the expertise and interests of the researcher. Clinical research is usually driven by the knowledge gaps or challenges faced by a clinician in day to day clinical practice. The range is vast, varying from help seeking behavior, diagnostic evaluation and efficacy of different interventions, to relapse prevention. When there is a barrier in accessing the health care facilities in diseases like mental illness, substance use disorders or other stigmatizing illnesses like leprosy, most of the patients can only be identified in epidemiological studies. Sometimes, the research 2is driven by the National Programs and policies of the government. As now-a-days research is gradually becoming an expensive affair, the availability of funds and the priority areas of the funding agencies are likely to influence the area of research. Recent trends in the research, supported by literature review, can also generate some ideas for a research study. The investigators should also decide whether to do multidisciplinary research or in one particular specialty, basic or applied research, quantitative or qualitative research, or research in health economics.
A good research topic should be Feasible, Interesting, Novel, Ethical and Relevant. These criteria have been called the FINER formula. After identifying an area for research, a detailed protocol is prepared. The protocol should explain what the research plans to achieve, how the topic of the study is important, and how the knowledge gained from this research can address the current knowledge gap in national and international scenarios. The research design should be formulated by taking into account the feasibility and practical aspects versus robustness or soundness of the methodology of the study which can answer the research question.
The protocol is a comprehensive action plan of the proposed research study, and needs to be prepared carefully and not in haste. The protocol is an essential part of a good quality research. It is required not only to get approval from ethics committee but is also a guiding tool for the whole research study. Writing a research protocol of high quality and relevance is also important to apply for funding a research. The research proposal is supported by findings from review of literature or from a pilot study. The protocol explains in detail the procedures to be carried out in the study, including the problems likely to occur during the conduct of the study and the methods to overcome them. The investigators need to discuss among themselves or with other colleagues in the respective field to improve or strengthen the proposal.
In studies where multiple investigators are involved, the role of individual investigators in the research study should be clearly delineated and all investigators should follow a uniform approach to maintain the fidelity. In a multicenter study 3or in a study which multiple investigators are involved or the funded projects, the publication protocol, order of authorship, dissemination of results, data sharing and data ownership should be clarified in the protocol. A good research study should strictly adhere to the protocol. Occasionally, the protocol may need modifications after the study has been started, due to change in circumstances or any other reason. If such a situation happens, approval would need to be taken from the ethics committee regarding the changes made, and details about the change and reason for making a change in the protocol would also need to be mentioned in the methodology as well as the results and the final report.
DEVELOPING A RESEARCH PROTOCOL
A typical protocol should have the following format:
- Title
- Abbreviations/Acronyms
- Introduction/Background
- Review of Literature
- Hypothesis/Research Questions
- Aims and Objectives
- Methodology
- Statistical Analysis
- Ethical Aspects
- References
- Appendices
The different components are discussed in detail in this section.
Title
As the title is the first thing to be noticed by the potential readers or target readers, it should be succinct and concise. The average length for a title is 10 to 12 words. It should be self-explanatory about the aims/objectives or the variables under investigation. As it is not always possible to mention all the features of the research project in the title, the most important points should to be highlighted. However, it may be revised after the study at the time of publication to reflect the purpose of the study more closely.4
After the title, names of the investigators and personnel involved in the study should be mentioned. This includes who will be the principal investigator, coprincipal investigator and coinvestigators, their affiliations and the institution (s)/sites where the study will be carried out.
For the purpose of this chapter, we will be using the example of a study that measures the plasma levels of omega-3 fatty acids in patients with depressive disorders and healthy controls. In this study, the title may be written as ‘A controlled study of plasma omega-3 fatty acids in patients with depressive disorders’.
Abbreviations and Acronyms
While some authors suggest making a list of abbreviations and acronyms, others suggest that the full name should be written along with the abbreviations and acronyms in the bracket when it appears first time in the text.
Some protocols, particularly the larger ones, include a synopsis or summary which summarizes all the elements of the protocol.
Introduction/Background
In this section, the subject matter of investigation, terminology, importance of the topic, and its need and implications are briefly described. This section needs to be carefully prepared and should include a subtle argument to convince the readers that the subject of research is essential and is a priority area. The introduction section can be conceptualized as the art of marketing the science. It should clearly explain that how the background knowledge led to the origin of this concept and proposal. The scientific rationale and relevance of this study in current scenario should be described.
Review of Literature
The literature review should support the rationale of the study. A correct and faithful description of the research status must be given. For this, a detailed literature search must be done from common databases like Pubmed, Embase, Scopus, MEDLINE, Google Scholar, etc. Details PubMed about the literature search are explained in chapter 2.5
While writing the review, attention should be drawn to the good points and deficiencies of the available studies. In terms of writing style, it is a good practice to make the writing flow rather than simply going through a list of papers. The current knowledge gap in the respective field should be highlighted here and how this piece of research can fulfill this knowledge gap needs to be mentioned. One may structure the review of literature under subheadings.
As per the example title given earlier, details about omega- 3 fatty acids, and their relevance to psychiatric illnesses, particularly depression, needs to be reviewed.
Based on the literature review and current understanding, research hypotheses or rationale for the study should be formulated. Example of rationale (as per the above study title): ‘There is no Indian data on relationship between omega-3 fatty acids and depression, or correlates of levels of omega-3 fatty acid level with severity of depression’.
Hypothesis/Research Questions
The research questions are carefully designed sentences about what a particular research intends to find out and explicitly reveal its purpose. The questions should be written directly, without giving the background information here. A passive voice is usually avoided. It is very important to avoid the ‘let us start a project and see what happens’ approach.
The hypothesis is a tentative prediction of presumed relationship between two or more variables. It reflects what result is expected from the research by the investigators. It guides the scientific inquiries and often follows directly with the question being asked or the theory being tested. It provides direction to the research design and assists in the collection, analysis and interpretation of data. The hypothesis should be stated in simple and understandable words. In general, hypotheses are stated in the null form, as a statement which states that no relationships or differences exist. Then the hypothesis of no significant difference is challenged. The result of statistical testing gives the probability that the hypothesis of no difference is true.6
An example of null hypothesis is, there is no difference in levels of plasma omega-3 fatty acids in patients with depressive disorders and healthy controls.
An alternate example of hypothesis could be, there is a difference in levels of plasma omega-3 fatty acids in patients with depressive disorders and healthy controls.
Or
The levels of plasma omega-3 fatty acids in patients with depressive disorders are lower than that of healthy controls.
Aims and Objectives
The purpose of the study or what the study is intended to achieve can be the aim of the study. The aims section is a broad statement describing the goals of the project or the overall purpose of the research project, followed by specific objectives. Specific objectives are statements that define the measurable outcomes and detail the main aim or purpose of the project. Both the aims and objectives should be related to the study's hypothesis. They should be measurable, achievable, realistic, and time-constrained. It is crucial that the aims and objectives have these features, because objectives provide reviewers of the protocol with a clear picture of what you want to accomplish, form the foundation for the rest of the proposal, and are used to assess the adequacy and appropriateness of the proposed methods. Objectives should be simple, specific, and stated in advance (not after the research is done). More than one objective can also be mentioned.
Example 1 (as per the example study title):
Primary objective: To study and compare plasma omega-3 acids levels in depressed subjects and healthy controls.
Secondary objective: To study the relation between plasma omega-3 fatty acids level and severity of depression.
Example 2
To determine whether or not a modality of intervention should be the part of a public health program can be the aim of a study. In this case, the primary objectives would be the 7degree of improvement with the intervention in the study population in comparison to the placebo group. The secondary objective would be to study the cost-effectiveness of this intervention.
Methodology
The methodology is the most important part of the protocol. But it is the easiest part of the protocol to prepare. It is all about what one plans to do. It should contain all the details of how each of the objectives will be addressed. This section must be detailed and have clear plans, and just not vague and generalized statements. Some reporting guidelines also can be referred while planning a methodology (CONSORT for clinical trials, STROBE for observational studies, PRISMA for systematic reviews and meta-analysis).
While writing the methods, fluency must be ensured. A common mistake that makes the write-up appear disjointed is use of both passive as well as active voice within the same section. One must stick to either the point of view of the experiment (passive voice) or the point of view of the experimenter (active voice) throughout a paragraph to ensure coherence. This section should have all the information, so that the reader who needs to replicate the study/experiment can do it without access to the detailed study protocol. The methodology can be presented in structured or unstructured format. Structured representation makes it clearer and objective for easier comparability between different studies. Though unstructured format lacks objectivity, it may be a better option for descriptive and qualitative studies.
In methodology, one needs to state the study design, study population, setting of the study, selection criteria, study procedure, data collection, assessments, and interventions, if any.
Study design: Choice of the study design depends upon the objectives of the study and the hypotheses. The design and methods of the proposed study should ideally be the most efficient way to deliver the aims and objectives. Broadly, a study can be experimental/interventional or observational; and cross-sectional or follow-up/longitudinal. The scientific 8reasons for adopting a particular design should be explained clearly.
Study site: One should give a brief description of the site of the study, staff, services and other facilities available.
Study population: Whether the proposed study design takes into account the issues of representativeness of the population, and whether the results of the study would be generalizable or transferable beyond the immediate research setting or not, should be examined. For example, a study done at the inpatient/outpatient setting of a tertiary care hospital cannot be extrapolated to the general population. This may be due to reasons like different sociodemographic and clinical profiles of patients, the location of the tertiary care hospital, the availability of expert health care professionals, etc. To determine a study design, the ethical issues should be taken care of too.
Study participants and selection criteria: Judging the external validity of a study involving human subjects, i.e. to whom the study results may be applied, requires that descriptive data be provided regarding the basic demographic profile of the sample population, including age, gender, and possibly the racial composition.
It is a general practice to refer the participants as patients. But, when we include a control group, they may not be patients. So, preferably, the term subjects can be used. The specific selection criteria of the participants should be defined here. The participants can be patients, healthy controls or general population (in case of epidemiological study), caregivers, or health care providers. The study settings/universe of the study too should be clearly mentioned. They can be subjects with a particular diagnosis, all the subjects attending the outpatient services, or inpatients. If the subjects belong to a particular diagnosis, it should be clearly operationalized as per standard practice guidelines or any standard reference or sometimes by proxy measures. For example, a stable patient may be defined as one who is on the same dose of medication for a particular period of time. The inclusion and exclusion criteria should be clearly mentioned, taking the possible biases into the account.9
In longitudinal studies, the strategies to address the confounding factors in selecting or allocating the participants and the attrition of subjects should also be described.
Dealing with biases: Biases (also called systematic errors) are the main target when selecting a study design and defining the methodological characteristics of the study. Methods and strategies to control and minimize systematic errors are the main factors affecting the validity of the study results and conclusions. The bias can be as follows:
- Selection bias refers to systematic errors associated with the selection of study participants or units of observation.
- Information bias refers to systematic errors associated with the measurement or classification of study variables and the methods and instruments used for that purpose.
- Confounding refers to a phenomenon where certain variables (called confounding variables) that are associated simultaneously with the outcome and predictors under study and interfere with the valid estimation of the true predictor's effect on the outcome. The validity of a study is judged by the degree to which its outcome can be attributed to manipulation of independent variables and not to the effects of confounding variables. However, confounding variables are hardly ever fully controlled. The study design must be defined, so as to control as many extraneous factors as possible, so that any potential cause-and-effect relationship between two objects can be judged validly.
Sampling: The sampling method also need to be mentioned. Sampling can be consecutive, randomized or convenient (purposive). This depends on the study objective and feasibility. For prevalence studies, consecutive sampling or randomized sampling should be done, and not convenient sampling. Sample size should be calculated based on the findings of the previous study by using statistical formula. A larger sample size than needed to test the research hypothesis increases the cost and duration of the study and will be unethical if it exposes human subjects to any potential unnecessary risk without additional benefit. A smaller sample size than 10needed can also be unethical if it exposes human subjects to risk with no benefit to scientific knowledge. The basis on which sample size is calculated should be explained in the methodology section of the protocol. The duration/timeline of the study should also be mentioned.
Recruitment process: Authors should describe in detail how recruitment will be undertaken and particularly how effective it is expected to be. The researchers should keep complete account of the subjects, i.e. number of participants approached, those who accepted and those that refused to participate, reasons for refusal and a brief characterization of the subjects refusing to participate. Methods to reduce refusal rate should also be described.
Study procedure: In this section, what exactly will be done in the research should be mentioned. The rationale and assumptions on which the study procedures are based should be stated in the methods section. Whenever it is not obvious, the purpose of a procedure should be stated in relationship either to the research question or to the entire protocol. In an interventional study, the details about the intervention, dose and duration of medications or a description of non-pharmacological interventions must be clearly mentioned. In nonpharmacological psychotherapeutic interventions, it would include the kind of therapy, and number, duration and frequency of sessions.
Data collection and assessments: The data collection method needs to be described in detail. The data collection tools include retrospective data (medical records), questionnaires, interviews (structured and semi-structured), laboratory tests and clinical examinations. The semi-structured proforma usually contains the sociodemographic and clinical information. The variables/information supposed to be collected depends on the literature review, and possible confounding/contributing/related factors to the subject studied. Variables should be operationally defined by indicating how the variable will be observed and measured in the study. Abstract variables (constructs), such as quality of life or 11stress, should be defined both conceptually and operationally. The conceptual definition explains the theoretical meaning of the variable, while the operational definition specifies how it will be measured.
Instruments or assessment methods used to study the objectives should be described. The cross-cultural variation, and validity and reliability of an instrument in a different language should be addressed. Details of the measurement procedures or instruments need to be given in detail.
In general, the variables in a study could be classified into four:
- Predictor (independent, exposure or intervention) variables,
- Outcome (dependent) variables,
- Confounding (extraneous) variables or
- Interaction (effect modifier) variables.
The main predictors and all outcome variables should be described with sufficient detail, so as to allow replication and assessment of the quality of the measurement or classification.
In some of the research projects, particularly the funded projects, certain specific issues also need to be specified. The project milestone can act as a guide or reminder to make the task time-bound. The methods of dissemination of research findings allow the readers to know how the results would be accessible to the research community. It can be through presentation in conferences, academic forums or through the publication in academic journals. In funded projects, the funding agency will release the funds for the project as per the milestone. Funds can also be allocated for dissemination of the research findings,. A list of all the resources likely to be required for successful completion of the project needs to be included in the protocol. The resources required can be personnel, instruments, stationary and contingencies. As the resources have cost implications, adequate justification must be given to the funding agency for the same.
Data Management and Statistical Analysis
As the clinical history and examination contain sensitive information, the privacy and confidentiality of the data should be maintained. Where and how the data are going to be stored 12and how long it should be kept and who all can access the data must be described, as it has both ethical and legal implications. In some cases, measures to deidentify the data are adopted. The data coding process should also be mentioned.
Exact methods planned and the tests to be used to analyze the data must be mentioned beforehand. It should not be the case that data analysis would be planned after collecting the data, as it can introduce bias. Details on how the primary and secondary outcomes will be analyzed should be included. The computer software that will be used for data analysis should also be mentioned.
The choice of statistical analysis is dependent on the purpose of investigation, mathematical characteristics of the variables involved, the method of data collection and the statistical assumptions made about these variables. Descriptive statistics can be used to summarize the data to describe the sample. Basic examples of numerical descriptors include the mean and standard deviation. Inferential statistics is used to model patterns in the data, accounting for randomness and drawing inferences about the larger population. These inferences may take the form of answers to yes/no questions (hypothesis testing), estimates of numerical characteristics (estimation), descriptions of association (correlation), or modeling of relationships (regression).
Ethical Aspects
At the beginning of the recruitment, informed consent must be taken from the study subjects. The participant information sheet should be written in such a language that the participants can read and understand clearly. There should not be any coercion or inducement. Being or not being a part of the study should not affect the usual treatment process. The name and identity of the study subjects must be kept confidential. If any invasive procedure or investigations are to be used, it should be clearly explained. In case of children and adolescents, consent from the parent or legal guardian should be taken. For children >7 years of age, assent should be taken. Similarly, in participants with impaired judgement (e.g.: acute psychosis, mental retardation, delirium, dementia), a proxy 13consent should be taken. The ethical issues are of utmost importance in clinical trials. Where a definitive treatment is available, a new modality of intervention should not be compared with a placebo but with an active comparator. When to break the blinding (e.g. in case of adverse events) must be clearly mentioned. The research should follow the principle of good clinical practice. Ethical clearance is mandatory from an appropriate authorized body before starting a research.
Internationally recognized ethical guidelines a include Declaration of Helsinki—a set of ethical principles regarding experimentation involving human subjects developed for the medical community by the World Medical Association; and the Indian Council of Medical research (ICMR) guidelines on research on human subjects (available from http://icmr.nic.in/ethical_guidelines.pdf).
Finance and Resources
Details about the funding agency should be mentioned. The budget would include a distribution of expenditure under different heads like manpower, instruments, travel, etc. Direct and indirect costs and overhead expenditure should be mentioned. The resources and facilities available in the place where the study is to be carried out should be mentioned. All clinical trials involving human subjects are to be registered in a public trial registry before the data collection process is started, and need to obtain the trial registration number.
References
References should be mentioned at the end of the protocol. This is important because the readers can follow-up a reference of interest. In the reference section, ideas and information taken from other researchers is acknowledged. There are two major types of referencing systems: Vancouver style and Harvard style. In the Vancouver system, references are numbered consecutively in the order of appearance in the text and identified by Arabic numerals in parenthesis or superscript. The references are then listed numerically at the end of the protocol. The structure of a journal article citation under the Vancouver system is authors’ surnames, initials, 14title of article, abbreviated name of journal, year, volume, issue (if applicable) and page numbers. If there are more than six authors, names of the first six are mentioned and followed by ‘et al.’. In Harvard system, within the text, the author and year are mentioned. In the bibliography, the sequencing is done alphabetically. The structure of the full citation of a journal article under the Harvard system is author surname, initials, year, title of article, full name of journal, volume, issue (if applicable) and page numbers. The usage of ‘et al.’ applies after three authors.
Appendices
Any proforma (structured/semistructured), scales or instruments proposed to be used in the study can be given as appendices.
SUGGESTED READING
- Arora SK, Shah D. Writing Methods: How to Write, What You Did? Indian Pediatrics. 2016;53:335–40.
- Freeman C, Tyrer P (Eds.) Research Methods in Psychiatry. 3rd Edition London, The Royal College of Psychiatrists; 2006.
- Galin J, Ognibene F, Johnson LL (Eds.). Principles and Practice of Clinical Research. 4th Edition, Elsevier; 2017.
- Reddy MV. Statistical Methods in Psychiatry Research and SPSS. Toronto, Apple Academic Press; 2015.