case study and case control study

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Case-control and Cohort studies: A brief overview

Posted on 6th December 2017 by Saul Crandon

Introduction

Case-control and cohort studies are observational studies that lie near the middle of the hierarchy of evidence . These types of studies, along with randomised controlled trials, constitute analytical studies, whereas case reports and case series define descriptive studies (1). Although these studies are not ranked as highly as randomised controlled trials, they can provide strong evidence if designed appropriately.

Case-control studies

Case-control studies are retrospective. They clearly define two groups at the start: one with the outcome/disease and one without the outcome/disease. They look back to assess whether there is a statistically significant difference in the rates of exposure to a defined risk factor between the groups. See Figure 1 for a pictorial representation of a case-control study design. This can suggest associations between the risk factor and development of the disease in question, although no definitive causality can be drawn. The main outcome measure in case-control studies is odds ratio (OR) .

Figure 1. Case-control study design.

Cases should be selected based on objective inclusion and exclusion criteria from a reliable source such as a disease registry. An inherent issue with selecting cases is that a certain proportion of those with the disease would not have a formal diagnosis, may not present for medical care, may be misdiagnosed or may have died before getting a diagnosis. Regardless of how the cases are selected, they should be representative of the broader disease population that you are investigating to ensure generalisability.

Case-control studies should include two groups that are identical EXCEPT for their outcome / disease status.

As such, controls should also be selected carefully. It is possible to match controls to the cases selected on the basis of various factors (e.g. age, sex) to ensure these do not confound the study results. It may even increase statistical power and study precision by choosing up to three or four controls per case (2).

Case-controls can provide fast results and they are cheaper to perform than most other studies. The fact that the analysis is retrospective, allows rare diseases or diseases with long latency periods to be investigated. Furthermore, you can assess multiple exposures to get a better understanding of possible risk factors for the defined outcome / disease.

Nevertheless, as case-controls are retrospective, they are more prone to bias. One of the main examples is recall bias. Often case-control studies require the participants to self-report their exposure to a certain factor. Recall bias is the systematic difference in how the two groups may recall past events e.g. in a study investigating stillbirth, a mother who experienced this may recall the possible contributing factors a lot more vividly than a mother who had a healthy birth.

A summary of the pros and cons of case-control studies are provided in Table 1.

Table 1. Advantages and disadvantages of case-control studies.

Cohort studies

Cohort studies can be retrospective or prospective. Retrospective cohort studies are NOT the same as case-control studies.

In retrospective cohort studies, the exposure and outcomes have already happened. They are usually conducted on data that already exists (from prospective studies) and the exposures are defined before looking at the existing outcome data to see whether exposure to a risk factor is associated with a statistically significant difference in the outcome development rate.

Prospective cohort studies are more common. People are recruited into cohort studies regardless of their exposure or outcome status. This is one of their important strengths. People are often recruited because of their geographical area or occupation, for example, and researchers can then measure and analyse a range of exposures and outcomes.

The study then follows these participants for a defined period to assess the proportion that develop the outcome/disease of interest. See Figure 2 for a pictorial representation of a cohort study design. Therefore, cohort studies are good for assessing prognosis, risk factors and harm. The outcome measure in cohort studies is usually a risk ratio / relative risk (RR).

Figure 2. Cohort study design.

Cohort studies should include two groups that are identical EXCEPT for their exposure status.

As a result, both exposed and unexposed groups should be recruited from the same source population. Another important consideration is attrition. If a significant number of participants are not followed up (lost, death, dropped out) then this may impact the validity of the study. Not only does it decrease the study’s power, but there may be attrition bias – a significant difference between the groups of those that did not complete the study.

Cohort studies can assess a range of outcomes allowing an exposure to be rigorously assessed for its impact in developing disease. Additionally, they are good for rare exposures, e.g. contact with a chemical radiation blast.

Whilst cohort studies are useful, they can be expensive and time-consuming, especially if a long follow-up period is chosen or the disease itself is rare or has a long latency.

A summary of the pros and cons of cohort studies are provided in Table 2.

The Strengthening of Reporting of Observational Studies in Epidemiology Statement (STROBE)

STROBE provides a checklist of important steps for conducting these types of studies, as well as acting as best-practice reporting guidelines (3). Both case-control and cohort studies are observational, with varying advantages and disadvantages. However, the most important factor to the quality of evidence these studies provide, is their methodological quality.

• Song, J. and Chung, K. Observational Studies: Cohort and Case-Control Studies .  Plastic and Reconstructive Surgery.  2010 Dec;126(6):2234-2242.
• Ury HK. Efficiency of case-control studies with multiple controls per case: Continuous or dichotomous data .  Biometrics . 1975 Sep;31(3):643–649.
• von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.   Lancet 2007 Oct;370(9596):1453-14577. PMID: 18064739.

Saul Crandon

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No Comments on Case-control and Cohort studies: A brief overview

Very well presented, excellent clarifications. Has put me right back into class, literally!

Very clear and informative! Thank you.

very informative article.

Thank you for the easy to understand blog in cohort studies. I want to follow a group of people with and without a disease to see what health outcomes occurs to them in future such as hospitalisations, diagnoses, procedures etc, as I have many health outcomes to consider, my questions is how to make sure these outcomes has not occurred before the “exposure disease”. As, in cohort studies we are looking at incidence (new) cases, so if an outcome have occurred before the exposure, I can leave them out of the analysis. But because I am not looking at a single outcome which can be checked easily and if happened before exposure can be left out. I have EHR data, so all the exposure and outcome have occurred. my aim is to check the rates of different health outcomes between the exposed)dementia) and unexposed(non-dementia) individuals.

Very helpful information

Thanks for making this subject student friendly and easier to understand. A great help.

Thanks a lot. It really helped me to understand the topic. I am taking epidemiology class this winter, and your paper really saved me.

Happy new year.

Wow its amazing n simple way of briefing ,which i was enjoyed to learn this.its very easy n quick to pick ideas .. Thanks n stay connected

Saul you absolute melt! Really good work man

am a student of public health. This information is simple and well presented to the point. Thank you so much.

very helpful information provided here

really thanks for wonderful information because i doing my bachelor degree research by survival model

Quite informative thank you so much for the info please continue posting. An mph student with Africa university Zimbabwe.

Thank you this was so helpful amazing

Apreciated the information provided above.

So clear and perfect. The language is simple and superb.I am recommending this to all budding epidemiology students. Thanks a lot.

Great to hear, thank you AJ!

I have recently completed an investigational study where evidence of phlebitis was determined in a control cohort by data mining from electronic medical records. We then introduced an intervention in an attempt to reduce incidence of phlebitis in a second cohort. Again, results were determined by data mining. This was an expedited study, so there subjects were enrolled in a specific cohort based on date(s) of the drug infused. How do I define this study? Thanks so much.

thanks for the information and knowledge about observational studies. am a masters student in public health/epidemilogy of the faculty of medicines and pharmaceutical sciences , University of Dschang. this information is very explicit and straight to the point

Very much helpful

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• Chapter 8. Case-control and cross sectional studies

Case-control studies

Selection of cases, selection of controls, ascertainment of exposure, cross sectional studies.

• Chapter 1. What is epidemiology?
• Chapter 2. Quantifying disease in populations
• Chapter 3. Comparing disease rates
• Chapter 4. Measurement error and bias
• Chapter 5. Planning and conducting a survey
• Chapter 6. Ecological studies
• Chapter 7. Longitudinal studies
• Chapter 9. Experimental studies
• Chapter 10. Screening
• Chapter 11. Outbreaks of disease
• Chapter 12. Reading epidemiological reports
• Chapter 13. Further reading

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Information

Study Design 101: Case Control Study

• Case Report
• Case Control Study
• Cohort Study
• Randomized Controlled Trial
• Practice Guideline
• Systematic Review
• Meta-Analysis
• Helpful Formulas
• Finding Specific Study Types

A study that compares patients who have a disease or outcome of interest (cases) with patients who do not have the disease or outcome (controls), and looks back retrospectively to compare how frequently the exposure to a risk factor is present in each group to determine the relationship between the risk factor and the disease.

Case control studies are observational because no intervention is attempted and no attempt is made to alter the course of the disease. The goal is to retrospectively determine the exposure to the risk factor of interest from each of the two groups of individuals: cases and controls. These studies are designed to estimate odds.

Case control studies are also known as "retrospective studies" and "case-referent studies."

• Good for studying rare conditions or diseases
• Less time needed to conduct the study because the condition or disease has already occurred
• Lets you simultaneously look at multiple risk factors
• Useful as initial studies to establish an association
• Can answer questions that could not be answered through other study designs

Disadvantages

• Retrospective studies have more problems with data quality because they rely on memory and people with a condition will be more motivated to recall risk factors (also called recall bias).
• Not good for evaluating diagnostic tests because it's already clear that the cases have the condition and the controls do not
• It can be difficult to find a suitable control group

Design pitfalls to look out for

Care should be taken to avoid confounding, which arises when an exposure and an outcome are both strongly associated with a third variable. Controls should be subjects who might have been cases in the study but are selected independent of the exposure. Cases and controls should also not be "over-matched."

Is the control group appropriate for the population? Does the study use matching or pairing appropriately to avoid the effects of a confounding variable? Does it use appropriate inclusion and exclusion criteria?

Fictitious Example

There is a suspicion that zinc oxide, the white non-absorbent sunscreen traditionally worn by lifeguards is more effective at preventing sunburns that lead to skin cancer than absorbent sunscreen lotions. A case-control study was conducted to investigate if exposure to zinc oxide is a more effective skin cancer prevention measure. The study involved comparing a group of former lifeguards that had developed cancer on their cheeks and noses (cases) to a group of lifeguards without this type of cancer (controls) and assess their prior exposure to zinc oxide or absorbent sunscreen lotions.

This study would be retrospective in that the former lifeguards would be asked to recall which type of sunscreen they used on their face and approximately how often. This could be either a matched or unmatched study, but efforts would need to be made to ensure that the former lifeguards are of the same average age, and lifeguarded for a similar number of seasons and amount of time per season.

Real-life Examples

Boubekri, M., Cheung, I., Reid, K., Wang, C., & Zee, P. (2014). Impact of windows and daylight exposure on overall health and sleep quality of office workers: a case-control pilot study. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine, 10 (6), 603-611. https://doi.org/10.5664/jcsm.3780

This pilot study explored the impact of exposure to daylight on the health of office workers (measuring well-being and sleep quality subjectively, and light exposure, activity level and sleep-wake patterns via actigraphy). Individuals with windows in their workplaces had more light exposure, longer sleep duration, and more physical activity. They also reported a better scores in the areas of vitality and role limitations due to physical problems, better sleep quality and less sleep disturbances.

Togha, M., Razeghi Jahromi, S., Ghorbani, Z., Martami, F., & Seifishahpar, M. (2018). Serum Vitamin D Status in a Group of Migraine Patients Compared With Healthy Controls: A Case-Control Study. Headache, 58 (10), 1530-1540. https://doi.org/10.1111/head.13423

This case-control study compared serum vitamin D levels in individuals who experience migraine headaches with their matched controls. Studied over a period of thirty days, individuals with higher levels of serum Vitamin D was associated with lower odds of migraine headache.

Related Formulas

• Odds ratio in an unmatched study
• Odds ratio in a matched study

Related Terms

A patient with the disease or outcome of interest.

Confounding

When an exposure and an outcome are both strongly associated with a third variable.

A patient who does not have the disease or outcome.

Matched Design

Each case is matched individually with a control according to certain characteristics such as age and gender. It is important to remember that the concordant pairs (pairs in which the case and control are either both exposed or both not exposed) tell us nothing about the risk of exposure separately for cases or controls.

Observed Assignment

The method of assignment of individuals to study and control groups in observational studies when the investigator does not intervene to perform the assignment.

Unmatched Design

The controls are a sample from a suitable non-affected population.

Now test yourself!

1. Case Control Studies are prospective in that they follow the cases and controls over time and observe what occurs.

a) True b) False

2. Which of the following is an advantage of Case Control Studies?

a) They can simultaneously look at multiple risk factors. b) They are useful to initially establish an association between a risk factor and a disease or outcome. c) They take less time to complete because the condition or disease has already occurred. d) b and c only e) a, b, and c

Evidence Pyramid - Navigation

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Factors for the development of anemia in patients with newly introduced olaparib: A retrospective case-control study

Affiliations.

• 1 Department of Pharmacy, Mie University Hospital, Mie, Japan.
• 2 Department of Obstetrics and Gynecology, Mie University School of Medicine, Mie, Japan.
• PMID: 37505180
• PMCID: PMC10378826
• DOI: 10.1097/MD.0000000000034123

Anemia is the most common dose-limiting toxicity of olaparib. However, few studies have analyzed the clinical features of olaparib-induced anemia. This study investigated the clinical features of olaparib-induced anemia. Additionally, the role of folate or vitamin B12 in olaparib-induced anemia was examined. This retrospective case-control study included patients who received olaparib at Mie University Hospital between January 2018 and December 2020. Data were collected between initiation of olaparib and discontinuation of olaparib or till December 2021. We investigated the development of grade ≥ 3 anemia during olaparib administration for at least 1 year. We examined patients with grade ≥ 3 anemia considering the mean corpuscular volume (MCV), its association with gastrointestinal events and cumulative dose of carboplatin. For the sub-study analysis, data on patients treated with olaparib for ovarian or endometrial cancer were collected to evaluate the Common Terminology Criteria for Adverse Events (CTCAE) or monthly changes in folate or vitamin B12 levels from baseline to 3 months after olaparib initiation. These data were collected between initiation of olaparib and discontinuation of olaparib or till November 2022. Patients with no data on folic acid or vitamin B12 levels were excluded from the sub-study. In the main study, 40 patients were included. Eighteen patients (45%) developed grade ≥ 3 anemia, and all patients discontinued treatment (94%) or reduced olaparib dose (67%) after developing anemia. Among the patients with grade ≥ 3 anemia, 9 (50%) exhibited macrocytic anemia and 15 (83%) had previously received carboplatin. The incidence of grade ≥ 2 dysgeusia was significantly higher in patients with grade ≥ 3 anemia (P = .034). Moreover, the cumulative dose of previously administered carboplatin was higher in patients who had 3 episodes of anemia (P = .102). In sub-study, 12 had data on folic acid and vitamin B12 levels. Sub-study analysis showed that none fulfilled the criteria for deficiency of folate or vitamin B12, while 3 developed grade 3 anemia. This study revealed that olaparib-induced anemia frequently occurs as macrocytic and normocytic erythroblastic anemia without folate or vitamin B12 deficiencies. A high cumulative dose of previously administered carboplatin and dysgeusia may be associated with olaparib-induced anemia.

Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.

• Anemia* / chemically induced
• Anemia* / complications
• Anemia* / epidemiology
• Carboplatin
• Case-Control Studies
• Folic Acid / therapeutic use
• Folic Acid Deficiency* / complications
• Hemoglobins / analysis
• Retrospective Studies
• Vitamin B 12 / therapeutic use
• Vitamin B 12 Deficiency* / complications
• Hemoglobins
• Vitamin B 12

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• Open access
• Published: 14 May 2024

The effect of preoperative use of anticoagulants on the hemostatic effect of intravenous application of tranexamic acid in PLIF: a case control study

• Shenshen Hao 1 ,
• Binbin Li 2 ,
• Shiying Luo 3 ,
• Shengli Dong 1 ,
• Shuai Liu 1 ,
• Hongke Li 1 &
• Xinhao Cao 4  

Scientific Reports volume  14 , Article number:  10997 ( 2024 ) Cite this article

Metrics details

• Medical research

Intravenous application of tranexamic acid (TXA) in posterior lumbar interbody fusion (PLIF) can effectively reduce blood loss without affecting coagulation function. However, it has not been reported whether preoperative use of anticoagulants may affect the efficacy of TXA in PLIF. The purpose of this study is to observe the effect of preoperative use of anticoagulants on coagulation indicators and blood loss after PLIF receiving intravenous unit dose TXA. A retrospective analysis was conducted on data from 53 patients with PLIF between 2020.11 and 2022.9, who received intravenous application of a unit dose of TXA (1 g/100 mL) 15 min before the skin incision after general anesthesia. Those who used anticoagulants within one week before surgery were recorded as the observation group, while those who did not use anticoagulants were recorded as the control group. The main observation indicators include surgical time, intraoperative blood loss, postoperative drainage volume, blood transfusion, and red blood cell (RBC), hemoglobin (HB), and hematocrit (HCT) measured on the 1st, 4th, 7th, and last-test postoperative days. Secondary observation indicators included postoperative incision healing, deep vein thrombosis of lower limbs, postoperative hospital stay, and activated partial thrombin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (FIB), and platelets (PLT) on the 1st and 4th days after surgery. The operation was successfully completed in both groups, the incision healed well after operation, and no lower limb deep vein thrombosis occurred. There was no significant difference in surgical time, intraoperative blood loss, postoperative drainage volume, and blood transfusion between the two groups ( p  > 0.05). There was no significant difference in the RBC, HB, and HCT measured on the 1st, 4th, 7th, and last-test postoperative days between the two groups ( p  > 0.05). There was no statistically significant difference in APTT, PT, TT, FIB and PLT between the two groups on the 1st and 4th postoperative days ( p  > 0.05). There was no significant difference in postoperative hospital stay between the two groups ( p  > 0.05). The use of anticoagulants within one week before surgery does not affect the hemostatic effect of intravenous unit dose TXA in PLIF.

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Introduction.

Posterior lumbar interbody fusion (PLIF) is a common and effective operation for the treatment of lumbar disc herniation (LDH), lumbar spinal stenosis (LSS), lumbar spondylolisthesis (LS) and other lumbar diseases 1 , 2 . However, it faces the challenge of massive perioperative blood loss 3 . Tranexamic acid (TXA) is a synthetic derivative of lysine, a synthetic anti fibrinolytic drug that could reduce surgical bleeding by inhibiting fibrinolysis and stabilizing blood clots 4 . Many studies have shown that intravenous TXA can effectively reduce perioperative blood loss in PLIF 5 , 6 , 7 , 8 . Meanwhile, in our previous studies, we confirmed that preoperative intravenous unit dose TXA in PLIF can safely and effectively reduce intraoperative and postoperative blood loss without affecting postoperative coagulation function indicators 9 , 10 .

However, in clinical practice, we have found such a phenomenon. Some patients who require surgery have a history of using anticoagulants for treatment before hospitalization. Therefore, it is inevitable to use anticoagulants before surgery to maintain treatment. In theory, the use of anticoagulants before surgery may increase perioperative blood loss. However, it is not yet known whether the hemostatic effect of TXA in PLIF may be affected by preoperative anticoagulant drugs. Therefore, this study mainly explores the following two issues. One is the safety of using anticoagulants within one week before surgery in PLIF receiving intravenous unit dose TXA. The other is the effect of using anticoagulants within one week before surgery on the hemostatic effect of TXA in PLIF.

Study design

This study was a retrospective, single center case control study. It was approved by NO.2021004, from the Ethics Committee of the General Hospital of Pingmei Shenma Medical Group. This study had been performed in accordance with the Declaration of Helsinki. The medical records were collected in the hospital, and the time range was 2020.11–2022.9. The inclusion criteria include: a . preoperative diagnosis of LDH, LSS, and LS, receiving standard PLIF treatment, b . general anesthesia, c . surgical segments ranging from 1 to 3, d . age range from 50 to 80 years, e . intravenous application of a unit dose of TXA (1 g/100 mL) (containing 100 mL normal saline and 1 g TXA) 15 min before the skin incision after anesthesia. Exclusion criteria include: a . pre-operative history of blood disease, b . preoperative history of deep vein thrombosis (DVT), c . lumbar surgery history, d . history of diabetes, e . intraoperative cerebrospinal fluid leakage or dural injury. Finally, 53 eligible cases were included. Among them, there are 21 males and 32 females, with an average age of (63.7 ± 8.5) years. The criteria for grouping were based on whether anticoagulants, such as low molecular weight heparin (LMWH) or indoprofen tablets, were used within one week before surgery. 25 cases of preoperative use of anticoagulants were recorded as the observation group, 28 cases were not applied and recorded as the control group. The intraoperative and postoperative measures of PLIF were similar. After surgery, two drainage tubes were placed and removed when the drainage flow rate was less than 50 mL/24 h. Postoperative routine use of antibiotics to prevent infection, corticosteroids to reduce spinal cord stress response, dehydration drugs to reduce edema response, non steroidal drugs to reduce pain, and LMWH drugs or indobufen tablets to prevent DVT.

Outcome indicators

Preoperative patient information was collected as baseline data. They included age, gender, body mass index (BMI), disease type, surgical segment, coexisting hypertension, prothrombin time (PT), activated partial thrombin time (APTT), thrombin time (TT), fibrinogen (FIB), platelets (PLT), hemoglobin (HB), red blood cell (RBC), and hematocrit (HCT).

The main observation indicators include surgical time, intraoperative blood loss, postoperative drainage volume, blood transfusion, and RBC, HB, and HCT measured on the 1st, 4th, 7th, and last-test postoperative days. The trend of changes in HB, RBC, and HCT during the perioperative period, represented by the median, was plotted using an Excel table.

Secondary observation indicators included postoperative incision healing, DVT of lower limbs, postoperative hospital stay, APTT, PT, TT, FIB, and PLT on the 1st and 4th postoperative days. The trend of changes in APTT, PT, TT, FIB, and PLT during the perioperative period was represented by the median, and a column chart was drawn using an Excel table.

Statistical methods

Data analysis was performed via SPSS statistical software (version 22.0). The econometric data which met the criteria was represented by mean ± standard deviation, and t-test was used for inter groups comparison. Non-conformities were represented by M [P25; P75], and comparisons between groups were conducted using Mann–Whitney U non-parametric tests. The counting data was expressed in the number of cases, and the Chi-squared test was used to compare between groups. The comparison of RBC, HB, HCT, APTT, PT, TT, FIB, and PLT between two groups measured on the 1st, 4th, 7th, and last-test postoperative days was conducted using a linear mixed model. P  < 0.05 was considered statistically significant.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the General Hospital of Pingmei Shenma Medical Group, and the reference number is 2021004. This study had been performed in accordance with the Declaration of Helsinki. All authors confirmed that informed consent was obtained from all subjects.

The comparison results of baseline data between the two groups

There was no significant differences in baseline data, concluding age, gender, BMI, disease type, surgical segment, coexisting hypertension, PT, APTT, TT, FIB, PLT, HB, RBC and HCT, between the two groups ( p  > 0.05), as shown in Table 1 .

The comparison of main observation indicators between the two groups

There was no significant difference in surgical time, intraoperative blood loss, postoperative drainage volume, and blood transfusion between the two groups ( p  > 0.05). There was no significant difference in the RBC, HB, and HCT measured on the 1st, 4th, 7th, and last-test postoperative days between the two groups ( p  > 0.05). The comparison was shown in Tables 2 and 3 , Figs. 1 , 2 and 3 .

The changes of RBC of the two groups, 10 12 /L.

The changes of HB of the two groups, g/L.

The changes of HCT of the two groups, L/L.

The comparison of secondary observation indicators between the two groups

The surgery was successfully completed in both groups of patients, with good postoperative incision healing and no occurrence of DVT. There was no significant difference in APTT, PT, TT, FIB and PLT between the two groups on the 1st and 4th postoperative days ( p  > 0.05). The comparison was shown in Table 4 , Figs. 4 , 5 , 6 , 7 and 8 .

The changes of PT of the two groups, s.

The changes of APTT of the two groups, s.

The changes of FIB of the two groups, g/L.

The changes of TT of the two groups, s.

The changes of PLT of the two groups, 10 9 /L.

The safety and feasible of PLIF have been recognized by spine surgeon and patients. There are four main reasons for bleeding in PLIF 11 . Firstly, the muscles in the surgical area of the lower back are very developed, so it is easy to bleed when peeling off the paraspinal muscles and soft tissues during surgery. Secondly, after decompression through laminectomy, the cancellous bone surface is prone to bleeding. Thirdly, when decompression enters the vertebral canal, it is easy to damage the intervertebral venous plexus and cause bleeding. Fourthly, when removing the intervertebral disc, it is necessary to scratch the upper and lower endplates, which is prone to bleeding. In addition, during surgery, a decrease in the number of coagulation factors and hyperfibrinolysis in patients can lead to significant intraoperative bleeding 12 . On the one hand, spine surgeon should consider the effect of PLIF, and on the other hand, consider how to reduce perioperative blood loss 13 . Many scholars have studied that intravenous TXA can safely and effectively reduce perioperative blood loss in PILF patients 5 , 6 , 7 , 8 . There are various options for using TXA during the perioperative period of spinal surgery, such as oral medication, local medication, intravenous medication, etc. 14 , 15 . However, the most commonly used method is intravenous administration 16 . In terms of medication timing, Yu et al. 17 suggested that during posterior lumbar surgery, intravenous administration of TXA 15 min before skin incision can reduce perioperative bleeding. This is because after about 15 min of intravenous application of TXA, it can reach and accumulate in the surgical area to effectively exert its hemostatic effect 18 . Therefore, in this study, TXA was chosen to be administered intravenously 15 min before PLIF. This usage is also one of the recommended methods in the Chinese Expert Consensus 19 .

In clinical practice, there are cases where some patients use anticoagulants before surgery. Vitamin K antagonists represented by Warfarin and antiplatelet drugs represented by aspirin will increase the risk of intraoperative bleeding, so these drugs are not used during perioperative preventive anticoagulation 20 . Heparins are widely used anticoagulants in clinical practice, mainly including ordinary heparin and LMWH. The relative molecular weight of LMWH is smaller than that of ordinary heparin, and it can only bind to antithrombin factor IIIa and cannot bind to factor IIa, thus possessing anti factor Xa effects 21 . LMWH can inhibit the activation of thrombin, thereby playing an anti-thrombotic role 22 . Meanwhile, compared to ordinary heparin, LMWH has a longer half-life, better bioavailability, better subcutaneous absorption, more stable pharmacokinetics, fewer adverse reactions such as bleeding, allergic reactions, and heparin induced thrombocytopenia, making it widely used in clinical practice 23 . Some studies have proved that the anticoagulant efficacy of factor Xa inhibitor represented by Rivaroxaban is consistent with LMWH, and does not increase the risk of serious bleeding, but it is currently mainly used after hip and knee joint replacement 24 , 25 . Indobufen, as a new generation of antiplatelet drugs, has good anticoagulant effects 26 . It can effectively inhibit the activity of platelet cyclooxygenase 1 , which is similar to the biochemical, functional and clinical effects of standard dose aspirin 27 . Indobufen tablets are oral medications and are more suitable for patients who are unwilling to receive subcutaneous injection of LMWH. Therefore, the anticoagulants used by the patients in this study were LMWH and indobufen tablets. In theory, for such patients, intraoperative and postoperative bleeding may increase.

However, the results of this study found that the intraoperative blood loss, postoperative drainage volume, and blood transfusion rate were similar in both groups. This indicates that for PLIF, TXA has a similar hemostatic effect in patients who use anticoagulants before surgery compared to those who do not. In order to further observe the possible correlation between the two types of drugs, namely synergistic or antagonistic effects. This study continuously observed RBC, HB, and HCT at different stages after surgery, and found no significant difference between the two groups, and both groups remained relatively stable. On the other hand, this suggests that the hemostatic effect of TXA in PLIF is not affected by the use of anticoagulants before surgery. It is worth noting that the PLIF surgical technique is already very mature, and the perioperative treatment measures are also very standardized. Moreover, both groups of patients in this study adopted similar treatment plans. These may be some of the possible reasons why the above indicators are similar. Therefore, further research is needed on the possible interrelationships between anticoagulants and TXA.

At the same time, patients receiving PLIF are mostly elderly people who require bed rest after surgery, and there are high-risk factors for thrombosis 28 . TXA, as an anti fibrotic hemostatic drug, may theoretically increase the risk of DVT 29 , 30 . The use of anticoagulants before surgery may affect postoperative coagulation function and recovery process. It is not yet known whether the simultaneous use of two types of drugs in a short period of time will have an impact on the safety of surgery. As is well known, surgical safety is a prerequisite for PLIF. Therefore, this study investigated the safety of surgery. In this study, not only were the surgeries completed safely in both groups, but there were no adverse events after the surgery, and the postoperative hospital stay was similar. Moreover, postoperative coagulation function indicators (APTT, PT, TT, FIB) and PLT were also similar. These indicate that preoperative use of anticoagulant drugs will not have adverse effects on the perioperative safety and postoperative recovery cycle of PLIF patients who have received intravenous TXA. There are two possible reasons for this phenomenon. Firstly, the fibrinolytic system and coagulation system are two independent systems, and there may be no related interference between anti-fibrinolytic and anticoagulant systems. Secondly, the sample size of this study is small and may have some bias. However, overall, TXA is safe and feasible for PLIF application in preoperative anticoagulant patients.

Through this study, two issues mentioned at the beginning were resolved. Firstly, it is safe and feasible to use anticoagulants within one week before surgery in PLIF with intravenous TXA. Secondly, the use of anticoagulants within one week before surgery did not affect the hemostatic effect of intravenous TXA on PLIF. However, this study is a single center, small sample retrospective medical record control study, and the reliability of its conclusions may inevitably be affected to some extent. Further research is needed to support the application of TXA in preoperative anticoagulation patients.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

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Project supported by Hainan Province Clinical Medical Center (No. 0202067). Scientific research project of General Hospital of Pingmei Shenma Medical Group (No. 4104022021180717).

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S. H. wrote the first draft of the article. B. L. critically reviewed drafts. S. L. critically edited drafts. S. D. diagnosed the patients. S. L. and H. L. treated the patient. C. X. has made substantial contributions to the conception and designed of the manuscript. S. D., S. L. and H. L. followed up the patients. All authors read and approved the final manuscript.

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Hao, S., Li, B., Luo, S. et al. The effect of preoperative use of anticoagulants on the hemostatic effect of intravenous application of tranexamic acid in PLIF: a case control study. Sci Rep 14 , 10997 (2024). https://doi.org/10.1038/s41598-024-60440-9

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Methodology Series Module 2: Case-control Studies

Maninder singh setia.

Epidemiologist, MGM Institute of Health Sciences, Navi Mumbai, Maharashtra, India

Case-Control study design is a type of observational study. In this design, participants are selected for the study based on their outcome status. Thus, some participants have the outcome of interest (referred to as cases), whereas others do not have the outcome of interest (referred to as controls). The investigator then assesses the exposure in both these groups. The investigator should define the cases as specifically as possible. Sometimes, definition of a disease may be based on multiple criteria; thus, all these points should be explicitly stated in case definition. An important aspect of selecting a control is that they should be from the same ‘study base’ as that of the cases. We can select controls from a variety of groups. Some of them are: General population; relatives or friends; and hospital patients. Matching is often used in case-control control studies to ensure that the cases and controls are similar in certain characteristics, and it is a useful technique to increase the efficiency of the study. Case-Control studies can usually be conducted relatively faster and are inexpensive – particularly when compared with cohort studies (prospective). It is useful to study rare outcomes and outcomes with long latent periods. This design is not very useful to study rare exposures. Furthermore, they may also be prone to certain biases – selection bias and recall bias.

Introduction

Case-Control study design is a type of observational study design. In an observational study, the investigator does not alter the exposure status. The investigator measures the exposure and outcome in study participants, and studies their association.

In a case-control study, participants are selected for the study based on their outcome status. Thus, some participants have the outcome of interest (referred to as cases), whereas others do not have the outcome of interest (referred to as controls). The investigator then assesses the exposure in both these groups. Thus, by design, in a case-control study the outcome has to occur in some of the participants that have been included in the study.

As seen in Figure 1 , at the time of entry into the study (sampling of participants), some of the study participants have the outcome (cases) and others do not have the outcome (controls). During the study procedures, we will examine the exposure of interest in cases as well as controls. We will then study the association between the exposure and outcome in these study participants.

Example of a case-control study

Examples of Case-Control Studies

Smoking and lung cancer study.

In their landmark study, Doll and Hill (1950) evaluated the association between smoking and lung cancer. They included 709 patients of lung carcinoma (defined as cases). They also included 709 controls from general medical and surgical patients. The selected controls were similar to the cases with respect to age and sex. Thus, they included 649 males and 60 females in cases as well as controls.

They found that only 0.3% of males were non-smokers among cases. However, the proportion of non-smokers among controls was 4.2%; the different was statistically significant ( P = 0.00000064). Similarly they found that about 31.7% of the female were non-smokers in cases compared with 53.3% in controls; this difference was also statistically significant (0.01< p <0.02).

Melanoma and tanning (Lazovic et al ., 2010)

The authors conducted a case-control study to study the association between melanoma and tanning. The 1167 cases - individuals with invasive cutaneous melanoma – were selected from Minnesota Cancer Surveillance System. The 1101 controls were selected randomly from Minnesota State Driver's License list; they were matched for age (+/- 5 years) and sex.

The data were collected by self administered questionnaires and telephone interviews. The investigators assessed the use of tanning devices (using photographs), number of years, and frequency of use of these devices. They also collected information on other variables (such as sun exposure; presence of freckles and moles; and colour of skin, hair, among other exposures.

They found that melanoma was higher in individuals who used UVB enhances and primarily UVA-emitting devices. The risk of melanoma also increased with increase in years of use, hours of use, and sessions.

Risk factors for erysipelas (Pitché et al, 2015)

Pitché et al (2015) conducted a case-control study to assess the factors associated with leg erysipelas in sub-Saharan Africa. This was a multi-centre study; the cases and controls were recruited from eight countries in sub-Saharan Africa.

They recruited cases of acute leg cellulitis in these eight countries. They recruited two controls for each case; these were matched for age (+/- 5 years) and sex. Thus, the final study has 364 cases and 728 controls. They found that leg erysipelas was associated with obesity, lympoedema, neglected traumatic wound, toe-web intertrigo, and voluntary cosmetic depigmentation.

We have provided details of all the three studies in the bibliography. We strongly encourage the readers to read the papers to understand some practical aspects of case-control studies.

Selection of Cases and Controls

Selection of cases and controls is an important part of this design. Wacholder and colleagues (1992 a, b, and c) have published wonderful manuscripts on design and conduct of case-control of studies in the American Journal of Epidemiology. The discussion in the next few sections is based on these manuscripts.

Selection of case

The investigator should define the cases as specifically as possible. Sometimes, definition of a disease may be based on multiple criteria; thus, all these points should be explicitly stated in case definition.

For example, in the above mentioned Melanoma and Tanning study, the researchers defined their population as any histologic variety of invasive cutaneous melanoma. However, they added another important criterion – these individuals should have a driver's license or State identity card. This probably is not directly related to the clinic condition, so why did they add this criterion? We will discuss this in detail in the next few paragraphs.

Selection of a control

The next important point in designing a case-control study is the selection of control patients.

In fact, Wacholder and colleagues have extensively discussed aspects of design of case control studies and selection of controls in their article.

According to them, an important aspect of selecting a control is that they should be from the same ‘study base’ as that of the cases. Thus, the pool of population from which the cases and controls will be enrolled should be same. For instance, in the Tanning and Melanoma study, the researchers recruited cases from Minnesota Cancer Surveillance System; however, it was also required that these cases should either have a State identity card or Driver's license. This was important since controls were randomly selected from Minnesota State Driver's license list (this also included the list of individuals who have the State identity card).

Another important aspect of a case-control study is that we should measure the exposure similarly in cases and controls. For instance, if we design a research protocol to study the association between metabolic syndrome (exposure) and psoriasis (outcome), we should ensure that we use the same criteria (clinically and biochemically) for evaluating metabolic syndrome in cases and controls. If we use different criteria to measure the metabolic syndrome, then it may cause information bias.

Types of Controls

We can select controls from a variety of groups. Some of them are: General population; relatives or friends; or hospital patients.

Hospital controls

An important source of controls is patients attending the hospital for diseases other than the outcome of interest. These controls are easy to recruit and are more likely to have similar quality of medical records.

However, we have to be careful while recruiting these controls. In the above example of metabolic syndrome and psoriasis, we recruit psoriasis patients from the Dermatology department of the hospital as controls. We recruit patients who do not have psoriasis and present to the Dermatology as controls. Some of these individuals have presented to the Dermatology department with tinea pedis. Do we recruit these individuals as controls for the study? What is the problem if we recruit these patients? Some studies have suggested that diabetes mellitus and obesity are predisposing factors for tinea pedis. As we know, fasting plasma glucose of >100 mg/dl and raised trigylcerides (>=150 mg/dl) are criteria for diagnosis of metabolic syndrome. Thus, it is quite likely that if we recruit many of these tinea pedis patients, the exposure of interest may turn out to be similar in cases and controls; this exposure may not reflect the truth in the population.

Relative and friend controls

Relative controls are relatively easy to recruit. They can be particularly useful when we are interested in trying to ensure that some of the measurable and non-measurable confounders are relatively equally distributed in cases and controls (such as home environment, socio-economic status, or genetic factors).

Another source of controls is a list of friends referred by the cases. These controls are easy to recruit and they are also more likely to be similar to the cases in socio-economic status and other demographic factors. However, they are also more likely to have similar behaviours (alcohol use, smoking etc.); thus, it may not be prudent to use these as controls if we want to study the effect of these exposures on the outcome.

Population controls

These controls can be easily conducted the list of all individuals is available. For example, list from state identity cards, voter's registration list, etc., In the Tanning and melanoma study, the researchers used population controls. They were identified from Minnesota state driver's list.

We may have to use sampling methods (such as random digit dialing or multistage sampling methods) to recruit controls from the population. A main advantage is that these controls are likely to satisfy the ‘study-base’ principle (described above) as suggested by Wacholder and colleagues. However, they can be expensive and time consuming. Furthermore, many of these controls will not be inclined to participate in the study; thus, the response rate may be very low.

Matching in a Case-Control Study

Matching is often used in case-control control studies to ensure that the cases and controls are similar in certain characteristics. For example, in the smoking and lung cancer study, the authors selected controls that were similar in age and sex to carcinoma cases. Matching is a useful technique to increase the efficiency of study.

’Individual matching’ is one common technique used in case-control study. For example, in the above mentioned metabolic syndrome and psoriasis, we can decide that for each case enrolled in the study, we will enroll a control that is matched for sex and age (+/- 2 years). Thus, if 40 year male patient with psoriasis is enrolled for the study as a case, we will enroll a 38-42 year male patient without psoriasis (and who will not be excluded for other reason) as controls.

If the study has used ‘individual matching’ procedures, then the data should also reflect the same. For instance, if you have 45 males among cases, you should also have 45 males among controls. If you show 60 males among controls, you should explain the discrepancy.

Even though matching is used to increase the efficiency in case-control studies, it may have its own problems. It may be difficult to fine the exact matching control for the study; we may have to screen many potential enrollees before we are able to recruit one control for each case recruited. Thus, it may increase the time and cost of the study.

Nonetheless, matching may be useful to control for certain types of confounders. For instance, environment variables may be accounted for by matching controls for neighbourhood or area of residence. Household environment and genetic factors may be accounted for by enrolling siblings as controls.

If we use controls from the past (time period when cases did not occur), then the controls are sometimes referred to historic controls. Such controls may be recruited from past hospital records.

Strengths of a Case-Control Study

• Case-Control studies can usually be conducted relatively faster and are inexpensive – particularly when compared with cohort studies (prospective)
• It is useful to study rare outcomes and outcomes with long latent periods. For example, if we wish to study the factors associated with melanoma in India, it will be useful to conduct a case-control study. We will recruit cases of melanoma as cases in one study site or multiple study sites. If we were to conduct a cohort study for this research question, we may to have follow individuals (with the exposure under study) for many years before the occurrence of the outcome
• It is also useful to study multiple exposures in the same outcome. For example, in the metabolic syndrome and psoriasis study, we can study other factors such as Vitamin D levels or genetic markers
• Case-control studies are useful to study the association of risk factors and outcomes in outbreak investigations. For instance, Freeman and colleagues (2015) in a study published in 2015 conducted a case-control study to evaluate the role of proton pump inhibitors in an outbreak of non-typhoidal salmonellosis.

Limitations of a Case-control Study

• The design, in general, is not useful to study rare exposures. It may be prudent to conduct a cohort study for rare exposures

Since the investigator chooses the number of cases and controls, the proportion of cases may not be representative of the proportion in the population. For instance if we choose 50 cases of psoriasis and 50 controls, the prevalence of proportion of psoriasis cases in our study will be 50%. This is not true prevalence. If we had chosen 50 cases of psoriasis and 100 controls, then the proportion of the cases will be 33%.

• The design is not useful to study multiple outcomes. Since the cases are selected based on the outcome, we can only study the association between exposures and that particular outcome
• Sometimes the temporality of the exposure and outcome may not be clearly established in case-control studies
• The case-control studies are also prone to certain biases

If the cases and controls are not selected similarly from the study base, then it will lead to selection bias.

• Odds Ratio: We are able to calculate the odds ratios (OR) from a case-control study. Since we are not able to measure incidence data in case-control study, an odds ratio is a reasonable measure of the relative risk (under some assumptions). Additional details about OR will be discussed in the biostatistics section.

The OR in the above study is 3.5. Since the OR is greater than 1, the outcome is more likely in those exposed (those who are diagnosed with metabolic syndrome) compared with those who are not exposed (those who do are not diagnosed with metabolic syndrome). However, we will require confidence intervals to comment on further interpretation of the OR (This will be discussed in detail in the biostatistics section).

• Other analysis : We can use logistic regression models for multivariate analysis in case-control studies. It is important to note that conditional logistic regressions may be useful for matched case-control studies.

Calculating an Odds Ratio (OR)

Hypothetical study of metabolic syndrome and psoriasis

Additional Points in A Case-Control Study

How many controls can i have for each case.

The most optimum case-to-control ratio is 1:1. Jewell (2004) has suggested that for a fixed sample size, the chi square test for independence is most powerful if the number of cases is same as the number of controls. However, in many situations we may not be able recruit a large number of cases and it may be easier to recruit more controls for the study. It has been suggested that we can increase the number of controls to increase statistical power (if we have limited number of cases) of the study. If data are available at no extra cost, then we may recruit multiple controls for each case. However, if it is expensive to collect exposure and outcome information from cases and controls, then the optimal ratio is 4 controls: 1 case. It has been argued that the increase in statistical power may be limited with additional controls (greater than four) compared with the cost involved in recruiting them beyond this ratio.

I have conducted a randomised controlled trial. I have included a group which received the intervention and another group which did not receive the intervention. Can I call this a case-control study?

A randomised controlled trial is an experimental study. In contrast, case-control studies are observational studies. These are two different groups of studies. One should not use the word case-control study for a randomised controlled trial (even though you have a control group in the study). Every study with a control group is not a case-control study. For a study to be classified as a case-control study, the study should be an observational study and the participants should be recruited based on their outcome status (some have the disease and some do not).

Should I call case-control studies prospective or retrospective studies?

In ‘The Dictionary of Epidemiology’ by Porta (2014), the authors have suggested that even though the term ‘retrospective’ was used for case-control studies, the study participants are often recruited prospectively. In fact, the study on risk factors for erysipelas (Pitché et al ., 2015) was a prospective case case-control study. Thus, it is important to remember that the nature of the study (case-control or cohort) depends on the sampling method. If we sample the study participants based on exposure and move towards the outcome, it is a cohort study. However, if we sample the participants based on the outcome (some with outcome and some do not) and study the exposures in both these groups, it is a case-control study.

In case-control studies, participants are recruited on the basis of disease status. Thus, some of participants have the outcome of interest (referred to as cases), whereas others do not have the outcome of interest (referred to as controls). The investigator then assesses the exposure in both these groups. Case-control studies are less expensive and quicker to conduct (compared with prospective cohort studies at least). The measure of association in this type of study is an odds ratio. This type of design is useful for rare outcomes and those with long latent periods. However, they may also be prone to certain biases – selection bias and recall bias.

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