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BMC Musculoskeletal Disorders volume 25 , Article number: 699 ( 2024 ) Cite this article
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The task faced by surgeons becomes significantly more challenging when they encounter lower extremity bone defects due to a variety of causes requiring lengthening. The most discussed and successful approach is the Illizarov technique, or lengthening over a nail (LON):distraction osteogenesis is also widely performed with monoliteral external fixators and intramedullarylengthening nails have increasingly been used in the last decade.
The data were collected from PubMed, Cochrane Library, Embase, and the Web of Science for all available studies comparing the outcomes of Ilizarov technique alone and LON technique (from January 1, 1997, to November 30, 2023). The outcomes of interest encompassed the external fixation index (EFI) (month/cm), mean duration of follow-up (MFT) (month), length gained (LG) (cm), consolidation index (CIx) (month/cm), and bone healing index (BHI) (month/cm).Complications include pin tract infection rate (PTI), axial deviation rate (AD), occurrence of intramedullary infection (II), delayed consolidation rate (DC), as well as data categorized into three levels of problems, obstacles, and sequelae based on the severity of complications.Two reviewers independently assessed each study for quality and extracted data. The case–control or respective cohort studies were evaluated using the Newcastle–Ottawa scale (NOS) to determine their techniqueological rigor.The Cochrane Collaboration’s risk assessment tool was employed to perform quality evaluations for randomized controlled trials.
This review included thirteen studies comprising a total of 629 patients.The external fixation index (month/cm) was significantly smaller in the LON technique compared to the Ilizarov technique alone [Mean Difference(MD) = -29.59, 95% CI -39.68–-19.49, P < 0.00001].In terms of the mean follow-up time(month) (MD = -0.92, 95% CI -3.49–1.65, P = 0.57), length gained (cm) (MD = -0.87, 95%CI -2.80–1.07, P = 0.38), consolidation index (month/cm) (MD = 0.66, 95% CI -3.44–4.77, P = 0.75), and bone healing index (month/cm) (MD = -3.33, 95% CI -13.07–6.41, P = 0.5), there were no significant differences observed. The LON technique exhibited a lower incidence of axial deviation [Odds Ratio(OR) = 0.06, 95%CI 0.03–0.16, P < 0.00001] and pin tract infection (OR = 0.30, 95%CI 0.18–0.50, P < 0.00001) compared to the Ilizarov technique alone.The remaining complications, such as intramedullary infection rate (OR = 0.93, 95%CI 0.42–2.06, P = 0.85) and delayed consolidation rate(OR = 0.61, 95%CI 0.20–1.86, P = 0.38), did not exhibit statistically significant differences.Our findings demonstrated that the LON technique results in lower incidences of problems (38.5%vs.58.6%) and sequelae (16.6% vs.30.9%) when compared to the Ilizarov technique alone. However, the rates of obstacles (32.4% vs.32.3%) were comparable between the two methods.
Our findings indicate that patients treated with the LON technique experienced significantly shorter external fixation durations and a lower incidence of complications (e.g., pin tract infections and axial deviation) compared to those treated with the Ilizarov technique alone. Other outcome metrics showed no significant differences between the two techniques. However, the LON technique offers substantial benefits, including reduced external fixation times and increased comfort, which enhance patient compliance. In conclusion, the LON technique is a safe, reliable, and effective method for treating tibial and femoral defects.
Peer Review reports
Segmental long bone defects present significant challenges for limb reconstruction surgeons, necessitating bone transport procedures to address bone loss. Such defects may arise from open fractures [ 1 ], the excision of necrotic bone in chronic osteomyelitis [ 2 ], the need for truncation lengthening in cases of poliomyelitis deformities [ 3 ], and idiopathic short stature. A predominant cause is large segmental bone defects resulting from open trauma. Without further intervention, these defects are unlikely to heal. Unhealed defects severely impair the patient’s quality of life, lead to psychological issues, and hinder their integration into normal society.
Professor Ilizarov, a Soviet physician, pioneered the Ilizarov Technique in 1950 [ 4 , 5 , 6 ]. This method, founded on the principles of distraction osteogenesis, aims to lengthen limbs and correct discrepancies. It employs external fixators to enhance local vascular distribution while maintaining the limb’s weight-bearing capacity during bone transportation. The technique boasts a bone healing rate exceeding 90% and is extensively documented and utilized for bone transport and limb lengthening [ 7 , 8 ]. Nevertheless, the prolonged use of external fixators can cause significant discomfort, restricting patients’ ability to engage in early functional exercises and potentially leading to joint contractures [ 9 , 10 ]. This discomfort can psychologically affect patients, increasing frustration and reducing compliance. Moreover, the extended use of fine Kirschner wires that penetrate the limb and bone tissue is linked to a higher risk of pin tract infections [ 11 ].
Building upon the Ilizarov technique, various bone transfer methods have been developed to address bone defects in the lower extremities. These include the Lengthening Over Nailing (LON) technique [ 12 ], Lengthening and Then Nail (LATN) [ 13 ], and Lengthening and Then Plate (LATP) [ 14 ]. A study by Paley et al. [ 15 ] demonstrated the efficacy of the LON technique in treating lower extremity bone defects. This method reduces the duration of external fixator usage, offering a more convenient approach. Subsequent clinical applications have shown that employing the LON technique for bone defects caused by fractures or infections yields satisfactory results, notably decreasing the overall time required for external fixation, effectively repairing substantial bone defects, and minimizing related complications [ 16 , 17 , 18 ]. However, challenges persist with the LON technique, such as potential risks of intramedullary infection, intramedullary nail breakage, and locking screw failures [ 19 , 20 ].
Choosing the optimal treatment for lower-extremity bone defects continues to be a significant challenge for clinicians. While previous studies have compared the Ilizarov technique alone to the LATN technique, to date, no comprehensive meta-analysis or systematic review has specifically evaluated the efficacy and outcomes of the LON technique against the Ilizarov technique alone. The aim of this study is to conduct a comparative analysis of the efficacy and outcomes of the LON technique relative to the Ilizarov technique alone in treating lower extremity bone defects.
The prospero registration number is CRD42023482000.
The present article was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was conducted across English language databases, including PubMed, Web of Science, Cochrane Library, and Embase, using Medical Subject Headings (MESH) terms “Ilizarov Technique” and “Fracture Fixation, Intramedullary,” to identify relevant literature. The search included data up to November 30, 2023, with no restriction on the language of publication. In addition, a comprehensive manual search was conducted to retrieve additional eligible studies from paper-based sources, and all gray literature, as well as references cited in included articles, were carefully screened.
The criteria for inclusion were established as follows:
(1) The LON technique was used in the intervention technique and only the Ilizarov technique was used in the control technique; (2) the type of study consisted of a randomized controlled trial (RCT), a case–control study (CCS), a retrospective clinical study (RCS), or a prospective clinical study; (3) at least one of the following outcome measures was reported: external fixation index (EFI), mean follow-up time (MFT), length gained (LG), consolidation index (CIx), bone healing index (BHI), and complications such as axial deviation (AD), pin tract infection (PTI), intramedullary infection (II), delayed consolidation (DC), problems, obstacles, and sequelae data. These data are either fully or partially available.and (4)The etiology of bone defects in the literature included could be open fractures, defects due to chronic osteomyelitis, limb length discrepancies, or idiopathic short stature osteotomy defects, but complete control of chronic osteomyelitis was required. All bone defects gained a lengthening length of ≤ 8 cm.
The exclusion criteria were as follows:
(1) Non-peer-reviewed publications are excluded from consideration.(2) certain study designs, such as non-human trials, observational studies, case reports, case series, review articles, and letters to the editor, are not included in this analysis.(3) reviews, letters, and recommendations are also excluded from the scope of this study. (4) in cases where the full text cannot be obtained or the original data is incomplete, those sources will not be considered.
Two academics conducted independent literature reviews, with any disputes resolved by a third reviewer. The following data was extracted from the included studies: (1) first author names, study period, author country, study type, number of cases, and patients’ age; (2) external fixation index (EFI), mean follow-up time (MFT), length gained (LG), consolidation index (CIx), bone healing index (BHI), as well as complications such as axial deviation (AD), pin tract infection (PTI), intramedullary infection (II), delayed consolidation (DC), and problems, obstacles, or sequelae. Secondly, we gathered a range of secondary outcome measures, including the etiology of long bone defects, sex, age, duration of surgery, amount of blood loss, average time to achieve full weight-bearing status, mean size of bone defects, excellent and good functional outcomes assessment results, as well as evaluations for knee and ankle dorsiflexion contractures (Supplementary Material 1). The EFI, which calculates the ratio between the duration of external fixation (in months) and the total bone delivery size (in centimeters).Furthermore, in cases where the data were incomplete or ambiguous in the studies reviewed, efforts were made to establish communication with the respective investigators for clarification purposes.
The methodological quality of each included study was assessed by two independent reviewers using the Newcastle–Ottawa Scale (NOS) [ 21 ], a tool commonly employed for evaluating the quality of cohort and case–control studies. Within this assessment, one of the domains considered was case definition, which encompassed selecting study cohorts, comparing cohorts, and determining outcomes. A NOS score of ≥ 6 indicates high quality, with a maximum total score of 9. For randomized controlled trials, the Cochrane Collaboration’s risk assessment tool was utilized to conduct quality assessments.
The statistical data were calculated using the Review Manager software (Cochrane Collaboration, Copenhagen, Denmark) and Stata17 software (Stata Corp., College Station, TX, USA). Weighted mean difference (WMD) and 95% confidence interval (CI) were utilized for continuous variables (EFI, MFT, LG, CIx, and BHI), while odds ratios (OR) and 95% confidence intervals (CI) were employed for categorical variables (pin tract infection, axial deviation, intramedullary infection, and delayed consolidation). Weighted averages were employed to calculate aggregated data, which were subsequently presented as either numerical values or proportions based on the sample size of each individual study. We conducted meta-analyses for relevant outcomes in each study using inverse variance statistics to combine effect sizes and apply logarithmic transformations when necessary. The combined effect sizes were expressed as percentages of their respective 95% confidence intervals (CIs). Heterogeneity and the proportion of variation between studies were quantified using the I 2 statistic. I 2 values below 50%, between 50 and 75%, and above 75% were categorized as low, moderate, and high heterogeneity, respectively. A P-value ≥ 0.05 and an I 2 value < 50% indicated no statistical heterogeneity among the studies. A random-effects model was employed in cases of moderate or high heterogeneity; otherwise, a fixed-effects model was utilized. Sensitivity analysis was conducted to assess the robustness of the findings, if deemed necessary. Additionally, forest plots were employed to illustrate the results of each study and evaluate pooled estimates, respectively, while funnel plots were used to assess publication bias. The funnel plots were evaluated to identify potential publication bias. Funnel plots can only intuitively determine the presence of publication bias, and the results may be biased. This prompted us to perform the Begg test as a supplementary assessment.
The initial search yielded a total of 784 articles, with 248 retrieved from PubMed, 258 from Web of Science, 9 from Cochrane Library, and 266 from Embase. Furthermore, the manual search identified three studies that met the inclusion criteria. After removing duplicates, a total of 563 studies remained. Among these, 500 were excluded based on abstract and title screening. Subsequently, we retrieved the remaining 63 full-text papers for a more comprehensive analysis. Out of these, 50 papers were excluded due to various reasons, including outcome does not meet the request ( n = 33), inability to calculate results from available data ( n = 4), and missing data on key outcome indicators ( n = 13). The meta-analysis finally included thirteen articles (Fig. 1 ).
Literature searching procedure delineated in the form of a flow chart
Figure 1 shows the flowchart of the study selection process.
Thirteen studies were conducted across eight countries, including the United States (one study), Japan (one study), Turkey (two studies), the United Kingdom (one study), Russia (one study), China (three studies), South Korea (three studies), and Egypt (one study). In limb lengthening surgery, a total of 308 cases using the Ilizarov technique alone and 321 cases using the combined technique were identified.In the 13 included studies, the follow-up ranged from 15.3 to 70 months, and the mean age of the patients was 30 years. The indications for limb lengthening were categorized into four main types: open fractures, defects due to chronic osteomyelitis, limb length discrepancies, or idiopathic short-stature osteotomy defects.Five studies conducted by Paley [ 15 ], Burghardt, et al. [ 22 ] specialized in limb lengthening for post-traumatic bone defects. Two studies conducted by Eralp [ 23 ], Sen et al. [ 24 ], specialized in limb lengthening for bone defects causing chronic osteomyelitis. Three studies conducted by Song [ 25 ], Watanabe, et al. [ 20 ] specialized in limb lengthening for lower limb inequality. Three studies conducted by Park and Sun specialized in limb lengthening for idiopathic short stature.For more information on the characteristics of the included studies, see Supplementary Table 1.
All studies [ 15 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ], including 11 RCSs and 2 RCTs, were of high quality with NOS scores ≥ 6, involving 321 patients in the LON technique and 308 patients in the Ilizarov technique. The quality assessment and basic characteristics of the selected trials are shown in Tables 1 and 2 . The results of LON technique pooled and combined with Ilizarov technique are shown in Table 3 . According to the funnel plot (Fig. 4 A, B, C, D, E), the publication bias of some outcome indicators could not be directly judged. Therefore, we performed the Begg test, and the results showed that all outcome indicators had no publication bias.
External fixation index (efi).
The EFI was recorded in twelve studies[ 15 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Data were analyzed using a random-effects model, and forest plots showed high heterogeneity (I 2 = 96%, P < 0.00001), revealing a significant difference between the two techniques (MD = -29.59, [95% CI -39.68 to -19.49]; I 2 = 96%, P < 0.00001). A meta-analysis of these twelve studies demonstrated that the LON technique exhibited a lower EFI compared to the Ilizarov technique alone (Fig. 2 A). This finding holds clinical significance as it indicates that the duration of external fixation was shorter in the LON technique than in the Ilizarov technique. A visual assessment of the funnel plot indicated the presence of a slight publication bias (Fig. 4 A). However,the Begger’s test was not statistically significant ( P = 0.732).
Comparison of external fixation index results ( A ), mean follow-up time results ( B ), length gained results ( C ), consolidation index results ( D ), and bone healing index results ( E ) between the LON and Ilizarov techniques
Twelve studies[ 15 , 20 , 22 , 23 , 24 , 25 , 27 , 28 , 29 , 30 , 31 , 32 ] involving 479 patients (233 in the LON technique and 246 in the Ilizarov technique) reported the MFT. The pooled results demonstrated that there was no significant difference in MFT between the two treatment techniques (MD = -0.92, [95% CI -3.49–1.65]; I 2 = 61%; P = 0.48) with low heterogeneity (Fig. 2 B). The results of the data showed no statistical differences in MFT between the two techniques. A visual assessment of the funnel plot indicated the presence of a slight publication bias (Fig. 4 B). However, Begger’s test was not statistically significant ( P = 0.945).
We performed a meta-analysis comparing the LG in patients with the LON technique versus the Ilizarov technique, including ten studies[ 15 , 20 , 22 , 23 , 25 , 26 , 27 , 28 , 29 , 30 ]. The random-effects model analysis showed no significant difference between the LON and Ilizarov techniques (MD = -0.87, [95%CI -2.80–1.07]; I 2 = 97%; P = 0.38). The results of the data showed no significant difference in LG between the two techniques (Fig. 2 C). A visual assessment of the funnel plot indicated the presence of a slight publication bias (Fig. 4 C). However, Begger’s test was not statistically significant ( P = 1.00).
Six studies[ 15 , 20 , 22 , 23 , 27 , 28 ] reported CIx, including 233 patients. There were 126 patients in the LON technique and 107 patients in the Ilizarov technique. Heterogeneity analysis showed that there was no significant statistical heterogeneity between these studies (MD = 0.66, 95%CI -3.44–4.77; I 2 = 66%, P = 0.75). The results of the data showed no significant difference in CIx between the two techniques (Fig. 2 D).
Three studies [ 25 , 29 , 30 ] involving 110 patients (57 in the LON technique and 53 in the Ilizarov technique) reported the BHI. The pooled results demonstrated that there was no significant difference in BHI between the two treatment techniques (MD = -3.33, [95%CI -13.07–6.41]; I 2 = 12%; P = 0.50) with low heterogeneity (Fig. 2 E). Therefore, there were no statistical differences in BHI between the two techniques.
Thirteen studies [ 15 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] reported adverse events. Table 4 summarizes the incidence of axial deviation (AD), needle tract infection (PTI), intramedullary infection (II), and delayed consolidation (DC).
Nine[ 15 , 20 , 22 , 24 , 25 , 27 , 28 , 29 , 30 ] studies compared the rate of AD in patients with the LON technique versus the Ilizarov technique. Meta-analysis of these 9 studies showed that the rate of AD was significantly higher in the Ilizarov technique than that in the LON technique (56/158 vs. 4/168; OR 0.06, [95% CI 0.03–0.16]; I 2 = 0%; P < 0.00001) (Fig. 3 A).
Comparison of axial deviation results ( A ), pin tract infection results ( B ), intramedullary infection results ( C ), and delayed consolidation results ( D ) between the LON and Ilizarov techniques
A total of eleven studies [ 15 , 20 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] provided data comparing the PTI rate in patients with LON versus the Ilizarov technique. The meta-analysis revealed that patients with the Ilizarov technique dramatically increased the risk of PTI compared to patients with the LON technique (86/203vs.56/214;OR 0.30, [95%CI 0.18–0.50];I 2 = 47%; P < 0.00001) (Fig. 3 B). A visual assessment of the funnel plot indicated the presence of a slight publication bias (Fig. 4 D). However,the Begger’s test was not statistically significant ( P = 0.119).
Five studies [ 15 , 22 , 23 , 24 , 26 , 27 ] provided data comparing the intramedullary infection rate in patients in the LON technique versus the Ilizarov technique. The meta-analysis demonstrated that patients in the LON technique showed no statistically significant difference compared to the Ilizarov technique (12/108 vs.13/114; OR 0.93, [95% CI 0.42–2.06]; I 2 = 43%; P = 0.85) (Fig. 3 C).
Twelve studies [ 15 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ] reported delayed consolidation between LON technique patients and Ilizarov technique patients. The rate of delayed consolidation after surgery showed no statistical difference between LON technique patients and Ilizarov technique patients (24/211 vs. 36/217; OR 0.61, [95% CI 0.20–1.86]; I 2 = 56%; P = 0.38) (Fig. 3 D). A visual assessment of the funnel plot indicated the presence of a slight publication bias (Fig. 4 E). However, the Begger’s test was not statistically significant ( P = 0.837).
Funnel plots show the results of the external fixation index ( A ); mean follow-up time ( B ); length gained ( C ); pin tract infection ( D ); and delayed consolidation ( E )
When total heterogeneity is high and within-group heterogeneity is low, this indicates that the grouping factor is significant for heterogeneity.First, the article categorized the etiology of bone defects into defects due to open fractures, defects due to chronic osteomyelitis, and defects due to limb length discrepancy and idiopathic short stature osteotomies. In order to exclude the confounding factors mentioned above, the authors performed subgroup analyses of EFI, LG, MFT, and DC. The results showed that the four different etiologies were not significant factors in their heterogeneity (Table 5 ). Second, we conducted subgroup analyses of EFI, LG, MFT, and DC according to different regions, and the results showed that articles published in different regions were also not a significant factor in the heterogeneity of this study (Table 5 ). Finally, there may be other reasons for the source of heterogeneity, such as the fact that the literature is all retrospective studies and the included literature itself.
Sensitivity analyses were used to test the stability of the combined results. As shown, sensitivity results were stable for the external fixation index (Fig. 5 A), mean follow-up time (Fig. 5 B), length gained (Fig. 5 C), and consolidation index (Fig. 5 D), axial deviation (Fig. 6 A), pin tract infection (Fig. 6 B), intramedullary infection (Fig. 6 C), and delayed consolidation (Fig. 6 D).
Sensitivity analysis diagram of the external fixation index ( A ), mean follow-up time ( B ), length gained ( C ), and consolidation index ( D ) in high heterogeneity outcomes
Sensitivity analysis diagram of the axial deviation ( A ), pin tract infection ( B ), intramedullary infection ( C ), and delayed consolidation ( D ) in high heterogeneity outcomes
However, by manually eliminating the literature one by one by Revman, the heterogeneity decreased to 25% after removing the Park (2008) [ 29 ] literature in LG and 21% after removing the Sun (2011) [ 30 ] literature in DC. These two pieces of literature were the source of heterogeneity for their respective outcome indicators.The remaining outcome indicators, such as EFI, MFT, and CI, had high heterogeneity but stable results by subgroup analysis and sensitivity analysis.
Previous meta-analyses have highlighted the advantages of the LATN technique over the Ilizarov method alone. Sheridan et al. [ 33 ] utilized Kaplan–Meier survival curves to demonstrate that the mean time to external fixation removal in the Ilizarov-only group was 32.6 weeks (σ = 8.43, 95% CI 24.7–40.3), which is double that of the LATN group at 16.3 weeks (σ = 8.02, 95% CI 8.9–23.7), with a statistically significant difference ( P = 0.0015). Additionally, Xu (2017) et al. [ 34 ] reviewed four retrospective cohort studies, revealing that external fixation duration was significantly reduced in the LATN group compared to the Ilizarov group, along with enhanced postoperative bone healing and restoration of lower limb function. Thus, our study aims to further this comparison by analyzing the Modified LON technique against the Ilizarov method to provide objective evidence for treating lower extremity bone defects.
Of the 13 studies [ 15 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] reviewed, all focused on tibial or femoral defects. Our systematic evaluation found that the LON technique generally results in shorter external fixation times, a lower incidence of axial deviation, and fewer pin tract infections compared to the Ilizarov method alone. There were no significant differences between the two groups concerning lengthening length, mean follow-up time, consolidation time, and bone healing, aligning with the findings of 12 included studies [ 15 , 20 , 22 , 23 , 24 , 25 , 26 , 28 , 29 , 30 , 31 , 32 ]. Exceptionally, EL-Husseini et al. [ 27 ] reported a significantly longer mean consolidation time in the LON group.
The LON technique, specifically modified for tibial and femoral lengthening, is designed to shorten the duration of external fixation, promote early weight-bearing, prevent scab and newly formed bone breakage [ 10 , 35 ], thus enabling quicker resumption of daily activities. The primary difference between the two methods is that while the Ilizarov technique requires external fixation until consolidation is complete, the LON method only during the distraction phase, thereby reducing the overall duration of fixation [ 36 ]. In all literature concerning bone lengthening, the external fixation index has been a reliable measure of healing time. In a 2023 study by Xu [ 31 ], the mean EFI for the LON technique was 0.58 ± 0.07 (months/cm), significantly lower than the 0.73 ± 0.15 (months/cm) for the Ilizarov technique. Oh CW et al. [ 8 ] also reported shorter average external fixation times with the LON technique for bone transfer in tibial or femoral defects, noting that a low EFI was associated with immediate frame removal after a prolonged distraction phase, concluding that this technique facilitates a swift return to daily activities with minimal complications. Similarly, our study demonstrated a much longer mean external fixation time using the Ilizarov technique.
Across the reviewed literature, external fixation durations were consistently shorter with the LON technique compared to the Ilizarov method alone. To identify factors influencing this disparity, we investigated potential reasons for the reduced external fixation time associated with the LON technique. A plausible explanation is that bone reaming induces significant osteoinductive debris and restores, or even enhances, periosteal blood flow within days. This increased blood flow likely promotes periosteum formation, thereby facilitating and accelerating the bone healing process [ 37 , 38 ]. Moreover, the insertion of intramedullary nails appears to stimulate the production of small bone marrow proteins, such as VEGFA-10 [ 39 ], which aid in developing microvascular structures. Presently, mRNA corresponding to this protein has been detected in the marrow cavity. The combination of the Ilizarov method with intramedullary nailing has been shown to effectively promote bone healing. Rozbruch et al. [ 40 ] have demonstrated that reaming of the medullary cavity positively impacts distraction osteogenesis, though there is also evidence suggesting that medullary reaming can impair distraction osteogenesis.
In Guo’s (2012) study[ 28 ], excessive lengthening was found to cause malformation in regenerating bone. The literature indicates that higher percentages of bone lengthening correlate with increased risk of complications [ 41 ]. Kocaoglu et al. [ 42 ] established a threshold of 6 cm for total limb lengthening, beyond which the likelihood of complications increased. For defects exceeding 10 cm, trifocal segment transmission significantly reduced external fixator time and related complications [ 43 ]. In this study, the extent of lengthening reported in the literature was maintained within 8 cm, and a forest plot comparison revealed no significant differences in lengthening between the two groups, thereby discounting length as a confounding factor and strengthening the validity of the results. The LON technique maintains axial alignment and preserves normal force lines in the lower extremity bones. It has been documented that premature removal of the frame can result in secondary axial deviation. In this study, the incidence of axial deviation was markedly lower in the LON technique group than in the Ilizarov group, suggesting that early intramedullary nail fixation may prevent axial deviations.
Guo’s study (2012) [ 28 ] revealed a significant difference in the rate of pin tract infections between the Ilizarov and LON techniques (47.8% and 15.7%, respectively), with the Ilizarov group exhibiting a higher risk due to prolonged use of external fixation braces—a finding consistent with our results (OR = 0.32, 95% CI 0.12–0.85, P = 0.02).The LON technique has been associated with a significant risk of intramedullary infection, with reported incidence rates between 3 and 15%. To minimize this complication, it is advisable to prevent contact between the wire and intramedullary nails [ 15 , 44 ]. Despite these precautions, deep infections can still occur [ 45 ]. In our study, the rate of intramedullary infections was comparable between the LON and the Ilizarov techniques, with isolated infections observed in both. We hypothesized that these were not due to wire and nail contact but rather local infection spread at the osteotomy site. Other studies have suggested that patients undergoing the LATN technique are more prone to infection at the time of intramedullary nail implantation [ 40 ], as prolonged external fixator wear may lead to pin tract infections, thereby increasing the risk of deep infections upon intramedullary nail insertion [ 46 , 47 ]. Therefore, perioperative adverse events may be reduced with proper preoperative management of LATN techniques. During the perioperative period, pin tract infections should be aggressively managed to prevent deep infections in patients post-LATN [ 48 , 49 ]. However, Sheridan et al. [ 33 ] reported that neither LATN nor LATP techniques resulted in higher rates of deep infections.
This study also categorized complications encountered in both techniques using the Paley scoring system. Among the 13 studies reviewed [ 15 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ], Yang (2018) [ 32 ] and Xu (2023) [ 31 ] reported no problems, obstacles, or sequelae(Table 6 ). Our findings demonstrated that the LON technique results in lower incidences of problems (38.5%vs.58.6%) and sequelae (16.6% vs.30.9%) when compared to the Ilizarov technique alone. However, the rates of obstacles (32.4% vs.32.3%) were comparable between the two methods (Table 6 ). A random-effects meta-analysis of “problems” by Sheridan et al. [ 33 ] confirmed a significantly higher relative risk of problems with the Ilizarov technique (RR = 1.66, 95%CI 1.40–1.97, P < 0.001). Similarly, the relative risk of “sequelae” was also significantly higher with the Ilizarov technique (RR = 1.79, 95%CI 1.28–2.49, P = 0.001). However, for “obstacles,” there was no significant difference between the techniques (RR = 0.97, 95%CI 0.85–1.10, P = 0.621), aligning with our findings.
Optimal bone healing and the restoration of lower limb function are paramount in treating bone defects. Deniz G. et al. [ 50 ] achieved complete bone restoration (100%) and high functional recovery (90%) in limb lengthening using the LON technique. The timeframe for resuming previous activities was comparable between techniques, with no significant differences in physical activity limitations at the final follow-up, corroborating the bone healing outcomes observed in our study.
Several limitations must be considered when interpreting the results of this study. Firstly, we were unable to obtain detailed information on potential confounders, such as the number of previous surgeries, type of antibiotics, or other nonmeasurable factors (e.g., types of intramedullary nails). Secondly, some studies from over a decade ago may have employed different surgical concepts than those currently in use. Consequently, our study could not analyze these risk factors or outcomes with uniform criteria. Consequently, we could not uniformly analyze these risk factors or outcomes. Moreover, most of the included studies were retrospective cohort studies, with only two being randomized controlled trials. The small number of comparable studies resulted in insufficient data and variability in patient demographics, techniques, and reported outcomes. Therefore, additional prospective studies and tighter controls for confounding factors are essential to more accurately assess the clinical efficacy of the LON technique. These recognized limitations are inherent to all studies utilizing this database design and could be mitigated through prospective data collection.
All data generated or analyzed during this study is included in the Additional File.
Lengthening and then nail
Lengthening and the plate
External fixtor index
Mean follow-up time
Length gained
Consolidation index
Bone healing index
Pin tract infection
Intramedullart infection
Axial deviation
Weighted mean difference
Confidence interval
Newcastle–Ottawa Scale
Case–control studies
Retrospective cohort studies
Prospective cohort studies
Mean difference
Relative risk
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The authors are grateful to all authors who provided information of their studies.
Not applicable.
This study was funded by Tutor Project of Gansu University of Traditional Chinese Medicine (2023YXKY015), Lanzhou Science and Technology Plan (2023–2-11), Gansu province Science and Technology Plan (22JR5RA009), and Lanzhou Science and Technology Plan (2023-ZD-170).
Fei Tan and Cuixian Yang contributed equally to this work.
Department of Joint Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou, Gansu, China
Fei Tan, Jiankang Zeng, Jiahuan Li, Peijie Li, Yongjie Qiao, Jing Wang, Jiangming Zhang, Dong Xie, Shuo Ye & Shenghu Zhou
Gansu University of Chinese Medicine, Lanzhou, Gansu, China
Fei Tan, Jiankang Zeng, Jiahuan Li, Peijie Li, Jing Wang, Jiangming Zhang & Dong Xie
Zhengzhou University, Zhengzhou, Henan, China
Cuixian Yang
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Fei Tan, Cuixian Yang, and Shenghu Zhou conceived the study, participated in the study design, performed the statistical analysis, and drafted the manuscript. Fei Tan, Jiankang Zeng, Peijie Li Jiangming Zhang, and Jiahuan Li contributed to data collection and the statistical interpretation. Yongjie Qiao, Dong Xie, and Shenghu Zhou participated in the study design, and oversaw the manuscript drafting process. Jing Wang as well as Shuo Ye helped with the language. All authors reviewed the manuscript.
Correspondence to Shenghu Zhou .
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Tan, F., Yang, C., Zeng, J. et al. A systematic review and meta-analysis:comparing the efficacy of the Ilizarov technique alone with lengthening over a nail for lower extremity bone defects. BMC Musculoskelet Disord 25 , 699 (2024). https://doi.org/10.1186/s12891-024-07799-y
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DOI : https://doi.org/10.1186/s12891-024-07799-y
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Xiao‐meng wang.
1 Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou Guangdong, China
Zhi‐hao li, wen‐fang zhong, associated data.
Data sharing is not applicable to this article because no datasets were generated or analyzed during the current study.
With the explosive growth of medical information, it is almost impossible for healthcare providers to review and evaluate all relevant evidence to make the best clinical decisions. Meta‐analyses, which summarize all existing evidence and quantitatively synthesize individual studies, have become the best available evidence for informing clinical practice. This article introduces the common methods, steps, principles, strengths and limitations of meta‐analyses and aims to help healthcare providers and researchers obtain a basic understanding of meta‐analyses in clinical practice and research.
This article introduces the common methods, principles, steps, strengths and limitations of meta‐analyses and aims to help clinicians and researchers obtain a basic understanding of meta‐analyses in clinical practice and research.
With the explosive growth of medical information, it has become almost impossible for healthcare providers to review and evaluate all related evidence to inform their decision making. 1 , 2 Furthermore, the inconsistent and often even conflicting conclusions of different studies can confuse these individuals. Systematic reviews were developed to resolve such situations, which comprehensively and systematically summarize all relevant empirical evidence. 3 Many systematic reviews contain meta‐analysis, which use statistical methods to combine the results of individual studies. 4 Through meta‐analyses, researchers can objectively and quantitatively synthesize results from different studies and increase the statistical strength and precision for estimating effects. 5 In the late 1970s, meta‐analysis began to appear regularly in the medical literature. 6 Subsequently, a plethora of meta‐analyses have emerged and the growth is exponential over time. 7 When conducted properly, a meta‐analysis of medical studies is considered as decisive evidence because it occupies a top level in the hierarchy of evidence. 8
An understanding of the principles, performance, advantages and weaknesses of meta‐analyses is important. Therefore, we aim to provide a basic understanding of meta‐analyses for clinicians and researchers in the present article by introducing the common methods, principles, steps, strengths and limitations of meta‐analyses.
There are many types of meta‐analysis methods (Table 1 ). In this article, we mainly introduce five meta‐analysis methods commonly used in clinical practice.
Meta‐analysis methods
Methods | Definitions |
---|---|
Aggregate data meta‐analysis | Extracting summary results of studies available in published accounts |
Individual participant data meta‐analysis | Collecting individual participant‐level data from original studies |
Cumulative meta‐analysis | Adding studies to a meta‐analysis based on a predetermined order |
Network meta‐analysis | Combining direct and indirect evidence to compare the effectiveness between different interventions |
Meta‐analysis of diagnostic test accuracy | Identifying and synthesizing evidence on the accuracy of tests |
Prospective meta‐analysis | Conducting meta‐analysis for studies that specify research selection criteria, hypotheses and analysis, but for which the results are not yet known |
Sequential meta‐analysis | Combining the methodology of cumulative meta‐analysis with the technique of formal sequential testing, which can sequentially evaluate the available evidence at consecutive interim steps during the data collection |
Meta‐analysis of the adverse events | Following the basic meta‐analysis principles to analyze the incidences of adverse events of studies |
Although more information can be obtained based on individual participant‐level data from original studies, it is usually impossible to obtain these data from all included studies in meta‐analysis because such data may have been corrupted, or the main investigator may no longer be contacted or refuse to release the data. Therefore, by extracting summary results of studies available in published accounts, an aggregate data meta‐analysis (AD‐MA) is the most commonly used of all the quantitative approaches. 9 A study has found that > 95% of published meta‐analyses were AD‐MA. 10 In addition, AD‐MA is the mainstay of systematic reviews conducted by the US Preventive Services Task Force, the Cochrane Collaboration and many professional societies. 9 Moreover, AD‐MA can be completed relatively quickly at a low cost, and the data are relatively easy to obtain. 11 , 12 However, AD‐MA has very limited control over the data. A challenge with AD‐MA is that the association between an individual participant‐level covariate and the effect of the interventions at the study level may not reflect the individual‐level effect modification of that covariate. 13 It is also difficult to extract sufficient compatible data to undertake meaningful subgroup analyses in AD‐MA. 14 Furthermore, AD‐MA is prone to ecological bias, as well as to confounding from variables not included in the model, and may have limited power. 15
An individual participant data meta‐analysis (IPD‐MA) is considered the “gold standard” for meta‐analysis; this type of analysis collects individual participant‐level data from original studies. 15 Compared with AD‐MA, IPD‐MA has many advantages, including improved data quality, a greater variety of analytical types that can be performed and the ability to obtain more reliable results. 16 , 17
It is crucial to maintain clusters of participants within studies in the statistical implementation of an IPD‐MA. Clusters can be retained during the analysis using a one‐step or two‐step approach. 18 In the one‐step approach, the individual participant data from all studies are modeled simultaneously, at the same time as accounting for the clustering of participants within studies. 19 This approach requires a model specific to the type of data being synthesized and an appropriate account of the meta‐analysis assumptions (e.g. fixed or random effects across studies). Cheng et al . 20 proposed using a one‐step IPD‐MA to handle binary rare events and found that this method was superior to traditional methods of inverse variance, the Mantel–Haenszel method and the Yusuf‐Peto method. In the two‐step approach, the individual participant data from each study are analyzed independently for each separate study to produce aggregate data for each study (e.g. a mean treatment effect estimate and its standard error) using a statistical method appropriate for the type of data being analyzed (e.g. a linear regression model might be fitted for continuous responses, or a Cox regression might be applied for time‐to‐event data). The aggregate data are then combined to obtain an summary effect in the second step using a suitable model, such as weighting studies by the inverse of the variance. 21 For example, using a two‐step IPD‐MA, Grams et al . 22 found that apolipoprotein‐L1 kidney‐risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.
Compared to the two‐step approach, the one‐step IPD‐MA is recommended for small meta‐analyses 23 and, conveniently, must only specify one model; however, this requires careful distinction of within‐study and between‐study variability. 24 The two‐step IPD‐MA is more laborious, although it allows the use of traditional, well‐known meta‐analysis techniques in the second step, such as those used by the Cochrane Collaboration (e.g. the Mantel–Haenszel method).
Meta‐analyses are traditionally used retrospectively to review existing evidence. However, current evidence often undergoes several updates as new studies become available. Thus, updated data must be continuously obtained to simplify and digest the ever‐expanding literature. Therefore, cumulative meta‐analysis was developed, which adds studies to a meta‐analysis based on a predetermined order and then tracks the magnitude of the mean effect and its variance. 25 A cumulative meta‐analysis can be performed multiple times; not only can it obtain summary results and provide a comparison of the dynamic results, but also it can assess the impact of newly added studies on the overall conclusions. 26 For example, initial observational studies and systematic reviews and meta‐analyses suggested that frozen embryo transfer was better for mothers and babies; however, recent primary studies have begun to challenge these conclusions. 27 Maheshwari et al . 27 therefore conducted a cumulative meta‐analysis to investigate whether these conclusions have remained consistent over time and found that the decreased risks of harmful outcomes associated with pregnancies conceived from frozen embryos have been consistent in terms of direction and magnitude of effect over several years, with an increasing precision around the point estimates. Furthermore, continuously updated cumulative meta‐analyses may avoid unnecessary large‐scale randomized controlled trials (RCTs) and prevent wasted research efforts. 28
Although RCTs can directly compare the effectiveness of interventions, most of them compare the effectiveness of an intervention with a placebo, and there is almost no direct comparison between different interventions. 29 , 30 Network meta‐analyses comprise a relatively recent development that combines direct and indirect evidence to compare the effectiveness between different interventions. 31 Evidence obtained from RCTs is considered as direct evidence, whereas evidence obtained through one or more common comparators is considered as indirect evidence. For example, when comparing interventions A and C, direct evidence refers to the estimate of the relative effects between A and C. When no RCTs have directly compared interventions A and C, these interventions can be compared indirectly if both have been compared with B (placebo or some standard treatments) in other studies (forming an A–B–C “loop” of evidence). 32 , 33
A valid network meta‐analysis can correctly combine the relative effects of more than two studies and obtain a consistent estimate of the relative effectiveness of all interventions in one analysis. 34 This meta‐analysis may lead to a greater accuracy of estimating intervention effectiveness and the ability to compare all available interventions to calculate the rank of different interventions. 34 , 35 For example, phosphodiesterase type 5 inhibitors (PDE5‐Is) are the first‐line therapy for erectile dysfunction, although there are limited available studies on the comparative effects of different types of PDE5‐Is. 36 Using a network meta‐analysis, Yuan et al . 36 calculated the absolute effects and the relative rank of different PDE5‐Is to provide an overview of the effectiveness and safety of all PDE5‐Is.
Notably, a network meta‐analysis should satisfy the transitivity assumption, in which there are no systematic differences between the available comparisons other than the interventions being compared 37 ; in other words, the participants could be randomized to any of the interventions in a hypothetical RCT consisting of all the interventions included in the network meta‐analysis.
Sensitivity and specificity are commonly used to assess diagnostic accuracy. However, diagnostic tests in clinical practice are rarely 100% specific or sensitive. 38 It is difficult to obtain accurate estimates of sensitivity and specificity in small diagnostic accuracy studies. 39 , 40 Even in a large sample size study, the number of cases may still be small as a result of the low prevalence. By identifying and synthesizing evidence on the accuracy of tests, the meta‐analysis of diagnostic test accuracy (DTA) provides insight into the ability of medical tests to detect the target diseases 41 ; it also can provide estimates of test performance, allow comparisons of the accuracy of different tests and facilitate the identification of sources of variability. 42 For example, the FilmArray® (Biomerieux, Marcy‐l'Étoile, France) meningitis/encephalitis (ME) panel can detect the most common pathogens in central nervous system infections, although reports of false positives and false negatives are confusing. 43 Based on meta‐analysis of DTA, Tansarli et al . 43 calculated that the sensitivity and specificity of the ME panel were both > 90%, indicating that the ME panel has high diagnostic accuracy.
3.1. frame a question.
Researchers must formulate an appropriate research question at the beginning. A well‐formulated question will guide many aspects of the review process, including determining eligibility criteria, searching for studies, collecting data from included studies, structuring the syntheses and presenting results. 44 There are some tools that may facilitate the construction of research questions, including PICO, as used in clinical practice 45 ; PEO and SPICE, as used for qualitative research questions 46 , 47 ; and SPIDER, as used for mixed‐methods research. 48
It is crucial for researchers to formulate a search strategy in advance that includes inclusion and exclusion criteria, as well as a standardized data extraction form. The definition of inclusion and exclusion criteria depends on established question elements, such as publication dates, research design, population and results. A reasonable inclusion and exclusion criteria will reduce the risk of bias, increase transparency and make the review systematic. Broad criteria may increase the heterogeneity between studies, and narrow criteria may make it difficult to find studies; therefore, a compromise should be found. 49
To minimize bias and reduce hampered interpretation of outcomes, the search strategy should be as comprehensive as possible, employing multiple databases, such as PubMed, Embase, Cochrane Central Registry of Controlled Trials, Scopus, Web of Science and Google Scholar. 50 , 51 Removing language restrictions and actively searching for non‐English bibliographic databases may also help researchers to perform a comprehensive meta‐analysis. 52
The selection or rejection of the included articles should be guided by the criteria. 53 Two independent reviewers may screen the included articles, and any disagreements should be resolved by consensus through discussion. First, the titles and abstracts of all relevant searched papers should be read, and inclusion or exclusion criteria applied to determine whether these papers meet. Then, the full texts of the included articles should be reviewed once more to perform the rejection again. Finally, the reference lists of these articles should be searched to widen the research as much as possible. 54
A pre‐formed standardized data extraction form should be used to extract data of included studies. All data should be carefully converted using uniform standards. Simultaneous extraction by multiple researchers might also make the extracted data more accurate.
Checklists and scales are often used to assess the quality of articles. For example, the Cochrane Collaboration's tool 55 is usually used to assess the quality of RCTs, whereas the Newcastle Ottawa Scale 56 is one of the most common method to assess the quality of non‐randomized trials. In addition, Quality Assessment of Diagnostic Accuracy Studies 2 57 is often used to evaluate the quality of diagnostic accuracy studies.
Several methods have been proposed to detect and quantify heterogeneity, such as Cochran's Q and I 2 values. Cochran's Q test is used to determine whether there is heterogeneity in primary studies or whether the variation observed is due to chance, 58 but it may be underpowered because of the inclusion of a small number of studies or low event rates. 59 Therefore, p < 0.10 (not 0.05) indicates the presence of heterogeneity given the low statistical strength and insensitivity of Cochran's Q test. 60 Another common method for testing heterogeneity is the I 2 value, which describes the percentage of variation across studies that is attributable to heterogeneity rather than chance; this value does not depend on the number of studies. 61 I 2 values of 25%, 50% and 75% are considered to indicate low, moderate and high heterogeneity, respectively. 60
Fixed effects and random effects models are commonly used to estimate the summary effect in a meta‐analysis. 62 Fixed effects models, which consider the variability of the results as “random variation”, simply weight individual studies by their precision (inverse of the variance). Conversely, random effects models assume a different underlying effect for each study and consider this an additional source of variation that is randomly distributed. A substantial difference in the summary effect calculated by fixed effects models and random effects models will be observed only if the studies are markedly heterogeneous (heterogeneity p < 0.10) and the random effects model typically provides wider confidence intervals than the fixed effect model. 63 , 64
Several methods have been proposed to explore the possible reasons for heterogeneity. According to factors such as ethnicity, the number of studies or clinical features, subgroup analyses can be performed that divide the total data into several groups to assess the impact of a potential source of heterogeneity. Sensitivity analysis is a common approach for examining the sources of heterogeneity on a case‐by‐case basis. 65 In sensitivity analysis, one or more studies are excluded at a time and the impact of removing each or several studies is evaluated on the summary results and the between‐study heterogeneity. Sequential and combinatorial algorithms are usually implemented to evaluate the change in between‐study heterogeneity as one or more studies are excluded from the calculations. 66 Moreover, a meta‐regression model can explain heterogeneity based on study‐level covariates. 67
A funnel plot is a scatterplot that is commonly used to assess publication bias. In a funnel plot, the x ‐axis indicates the study effect and the y ‐axis indicates the study precision, such as the standard error or sample size. 68 , 69 If there is no publication bias, the plot will have a symmetrical inverted funnel; conversely, asymmetry indicates the possibility of publication bias.
A forest plot is a valid and useful tool for summarizing the results of a meta‐analysis. In a forest plot, the results from each individual study are shown as a blob or square; the confidence interval, usually representing 95% confidence, is shown as a horizontal line that passes through the square; and the summary effect is shown as a diamond. 70
There are four most important principles of meta‐analysis performance that should be emphasized. First, the search scope of meta‐analysis should be expanded as much as possible to contain all relevant research, and it is important to remove language restrictions and actively search for non‐English bibliographic databases. Second, any meta‐analysis should include studies selected based on strict criteria established in advance. Third, appropriate tools must be selected to evaluate the quality of evidence according to different types of primary studies. Fourth, the most suitable statistical model should be chosen for the meta‐analysis and a weighted mean estimate of the effect size should be calculated. Finally, the possible causes of heterogeneity should be identified and publication bias in the meta‐analysis must be assessed.
Meta‐analyses have several strengths. First, a major advantage is their ability to improve the precision of effect estimates with considerably increased statistical power, which is particularly important when the power of the primary study is limited as a result of the small sample size. Second, a meta‐analysis has more power to detect small but clinically significant effects and to examine the effectiveness of interventions in demographic or clinical subgroups of participants, which can help researchers identify beneficial (or harmful) effects in specific groups of patients. 71 , 72 Third, meta‐analyses can be used to analyze rare outcomes and outcomes that individual studies were not designed to test (e.g. adverse events). Fourth, meta‐analyses can be used to examine heterogeneity in study results and explore possible sources in case this heterogeneity would lead to bias from “mixing apples and oranges”. 73 Furthermore, meta‐analyses can compare the effectiveness of various interventions, supplement the existing evidence, and then offer a rational and helpful way of addressing a series of practical difficulties that plague healthcare providers and researchers. Lastly, meta‐analyses may resolve disputes caused by apparently conflicting studies, determine whether new studies are necessary for further investigation and generate new hypotheses for future studies. 7 , 74
6.1. missing related research.
The primary limitation of a meta‐analysis is missing related research. Even in the ideal case in which all relevant studies are available, a faulty search strategy can miss some of these studies. Small differences in search strategies can produce large differences in the set of studies found. 75 When searching databases, relevant research can be missed as a result of the omission of keywords. The search engine (e.g. PubMed, Google) may also affect the type and number of studies that are found. 76 Moreover, it may be impossible to identify all relevant evidence if the search scope is limited to one or two databases. 51 , 77 Finally, language restrictions and the failure to search non‐English bibliographic databases may also lead to an incomplete meta‐analysis. 52 Comprehensive search strategies for different databases and languages might help solve this issue.
Publication bias means that positive findings are more likely to be published and then identified through literature searches rather than ambiguous or negative findings. 78 This is an important and key source of bias that is recognized as a potential threat to the validity of results. 79 The real research effect may be exaggerated or even falsely positive if only published articles are included. 80 For example, based on studies registered with the US Food and Drug Administration, Turner et al . 81 reviewed 74 trials of 12 antidepressants to assess publication bias and its influence on apparent efficacy. It was found that antidepressant studies with favorable outcomes were 16 times more likely to be published than those with unfavorable outcomes, and the apparent efficacy of antidepressants increased between 11% and 69% when the non‐published studies were not included in the analysis. 81 Moreover, failing to identify and include non‐English language studies may also increase publication bias. 82 Therefore, all relevant studies should be identified to reduce the impact of publication bias on meta‐analysis.
Because many of the studies identified are not directly related to the subject of the meta‐analysis, it is crucial for researchers to select which studies to include based on defined criteria. Failing to evaluate, select or reject relevant studies based on stricter criteria regarding the study quality may also increase the possibility of selection bias. Missing or inappropriate quality assessment tools may lead to the inclusion of low‐quality studies. If a meta‐analysis includes low‐quality studies, its results will be biased and incorrect, which is also called “garbage in, garbage out”. 83 Strictly defined criteria for included studies and scoring by at least two researchers might help reduce the possibility of selection bias. 84 , 85
The best‐case scenario for meta‐analyses is the availability of individual participant data. However, most individual research reports only contain summary results, such as the mean, standard deviation, proportions, relative risk and odds ratio. In addition to the possibility of reporting errors, the lack of information can severely limit the types of analyses and conclusions that can be achieved in a meta‐analysis. For example, the unavailability of information from individual studies may preclude the comparison of effects in predetermined subgroups of participants. Therefore, if feasible, the researchers could contact the author of the primary study for individual participant data.
Although the studies included in a meta‐analysis have the same research hypothesis, there is still the potential for several areas of heterogeneity. 86 Heterogeneity may exist in various parts of the studies’ design and conduct, including participant selection, interventions/exposures or outcomes studied, data collection, data analyses and selective reporting of results. 87 Although the difference of the results can be overcome by assessing the heterogeneity of the studies and performing subgroup analyses, 88 the results of the meta‐analysis may become meaningless and even may obscure the real effect if the selected studies are too heterogeneous to be comparable. For example, Nicolucci et al . 89 conducted a review of 150 published randomized trials on the treatment of lung cancer. Their review showed serious methodological drawbacks and concluded that heterogeneity made the meta‐analysis of existing trials unlikely to be constructive. 89 Therefore, combining the data in meta‐analysis for studies with large heterogeneity is not recommended.
Funnel plots are appealing because they are a simple technique used to investigate the possibility of publication bias. However, their objective is to detect a complex effect, which can be misleading. For example, the lack of symmetry in a funnel plot can also be caused by heterogeneity. 90 Another problem with funnel plots is the difficulty of interpreting them when few studies are included. Readers may also be misled by the choice of axes or the outcome measure. 91 Therefore, in the absence of a consensus on how the plot should be constructed, asymmetrical funnel plots should be interpreted cautiously. 91
Researchers must make numerous judgments when performing meta‐analyses, 92 which inevitably introduces considerable subjectivity into the meta‐analysis review process. For example, there is often a certain amount of subjectivity when deciding how similar studies should be before it is appropriate to combine them. To minimize subjectivity, at least two researchers should jointly conduct a meta‐analysis and reach a consensus.
The explosion of medical information and differences between individual studies make it almost impossible for healthcare providers to make the best clinical decisions. Meta‐analyses, which summarize all eligible evidence and quantitatively synthesize individual results on a specific clinical question, have become the best available evidence for informing clinical practice and are increasingly important in medical research. This article has described the basic concept, common methods, principles, steps, strengths and limitations of meta‐analyses to help clinicians and investigators better understand meta‐analyses and make clinical decisions based on the best evidence.
CM designed and directed the study. XMW and XRZ had primary responsibility for drafting the manuscript. CM, ZHL, WFZ and PY provided insightful discussions and suggestions. All authors critically reviewed the manuscript for important intellectual content.
The authors declare that they have no conflicts of interest.
This work was supported by the Project Supported by Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2019 to CM) and the Construction of High‐level University of Guangdong (G820332010, G618339167 and G618339164 to CM). The funders played no role in the study design or implementation; manuscript preparation, review or approval; or the decision to submit the manuscript for publication.
Wang X‐M, Zhang X‐R, Li Z‐H, Zhong W‐F, Yang P, Mao C. A brief introduction of meta‐analyses in clinical practice and research . J Gene Med . 2021; 23 :e3312. 10.1002/jgm.3312 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Xiao‐Meng Wang and Xi‐Ru Zhang contributed equally to this work.
Antituberculosis drug-induced liver injury (ATDILI) is a significant problem of tuberculosis treatment. This systematic review and meta‑analysis aimed at evaluating the incidence and risk factors of ATDILI in adult patients with tuberculosis in India.
Five electronic databases were searched comprehensively for studies on Indian adult patients with tuberculosis investigating the incidence and/or risk factors of ATDILI. The relevant data was pooled in a random or fixed-effect model to calculate the pooled incidence with a 95% confidence interval (CI), standardized mean difference (MD) or odds ratio (OR).
Following the screening of 3221 records, 43 studies with 12,041 tuberculosis patients were finally included. Based on the random effect model, the pooled incidence of ATDILI was 12.6% (95% CI, 9.9–15.3%, p < 0.001, I 2 = 95.1%). The pooled incidence was higher in patients with daily treatment regimen compared to the thrice weekly regimen (16.5% vs. 3.5%). The concurrent hepatitis B or C infection, alcohol consumption and underlying chronic liver disease were associated with high incidence of ATDILI. The pooled incidence of acute liver failure (ALF) among ATDILI patients was 6.78% (95% CI 3.9–9.5%). Female gender (OR 1.24), older age (MD 0.26), lean body mass index (OR 3.8), hypoalbuminemia (OR 3.09), N-acetyltransferase slow acetylator genotypes (OR 2.3) and glutathione S-transferases M null mutation (OR 1.6) were found to be associated with an increased risk of ATDILI. The pooled mortality rate of ATDILI patients was 1.72% (95% CI 0.4–3.0%) overall and 71.8% (95% CI 49.3–94.2%) in case of ALF.
Overall, 12.6% patients of tuberculosis in India developed ATDILI when combination of first-line antituberculosis drugs was used. An average of 7% of ATDILI patients progressed to ALF which had a high mortality rate. Older age, female, poor nutritional status and some genetic polymorphisms were identified as significant risk factors.
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Ramesh Kumar, Abhishek Kumar, Rishabh Patel, Sabbu Surya Prakash, Sudhir Kumar, Himanshu Surya & Sudheer Marrapu
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Kumar, R., Kumar, A., Patel, R. et al. Incidence and risk factors of antituberculosis drug-induced liver injury in India: A systematic review and meta-analysis. Indian J Gastroenterol (2024). https://doi.org/10.1007/s12664-024-01643-w
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2.1 Step 1: defining the research question. The first step in conducting a meta-analysis, as with any other empirical study, is the definition of the research question. Most importantly, the research question determines the realm of constructs to be considered or the type of interventions whose effects shall be analyzed.
The graphical output of meta-analysis is a forest plot which provides information on individual studies and the pooled effect. Systematic reviews of literature can be undertaken for all types of questions, and all types of study designs. This article highlights the key features of systematic reviews, and is designed to help readers understand ...
A systematic review collects all possible studies related to a given topic and design, and reviews and analyzes their results [ 1 ]. During the systematic review process, the quality of studies is evaluated, and a statistical meta-analysis of the study results is conducted on the basis of their quality. A meta-analysis is a valid, objective ...
Meta-analysis would be used for the following purposes: To establish statistical significance with studies that have conflicting results. To develop a more correct estimate of effect magnitude. To provide a more complex analysis of harms, safety data, and benefits. To examine subgroups with individual numbers that are not statistically significant.
The various types of sources through which a given case is described may exhibit considerable differences in information quality, challenging the overall integrity of the results of a meta-analysis. 24 Studies appearing in more formal outlets, such as peer-reviewed journals, have been through some quality control providing a degree of ...
Systematic reviews aim to identify, evaluate, and summarize the findings of all relevant individual studies over a health-related issue, thereby making the available evidence more accessible to decision makers. The objective of this article is to introduce the primary care physicians about the concept of systematic reviews and meta-analysis ...
Definition. "A meta-analysis is a formal, epidemiological, quantitative study design that uses statistical methods to generalise the findings of the selected independent studies. Meta-analysis and systematic review are the two most authentic strategies in research. When researchers start looking for the best available evidence concerning ...
Meta-analysis is the quantitative, scientific synthesis of research results. Since the term and modern approaches to research synthesis were first introduced in the 1970s, meta-analysis has had a ...
Conclusions. A systematic review is an article that synthesizes available evidence on a certain topic utilizing a specific research question, pre-specified eligibility criteria for including articles, and a systematic method for its production. Whereas a meta-analysis is a quantitative, epidemiological study design used to assess the results of ...
Meta-analysis is a central method for knowledge accumulation in many scien-tic elds (Aguinis et al. 2011c; Kepes et al. 2013). Similar to a narrative review, it serves as a synopsis of a research question or eld. However, going beyond a narra-tive summary of key ndings, a meta-analysis adds value in providing a quantitative
Meta-analytical methods face particular challenges in research fields such as social and political research, where studies often rest primarily on qualitative and case study research. In such contexts, where research findings are less standardized and amenable to structured synthesis, the case survey method has been proposed as a means of data ...
Many judgements are required in the process of preparing a meta-analysis. Sensitivity analyses should be used to examine whether overall findings are robust to potentially influential decisions. Cite this chapter as: Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 10: Analysing data and undertaking meta-analyses.
Case study is unbounded and relies on gathering external information; case analysis is a self-contained subject of analysis. The scope of a case study chosen as a method of research is bounded. However, the researcher is free to gather whatever information and data is necessary to investigate its relevance to understanding the research problem.
Sometimes the results of all of the studies found and included in a systematic review can be summarized and expressed as an overall result. This is known as a meta-analysis. The overall outcome of the studies is often more conclusive than the results of individual studies. But it only makes sense to do a meta-analysis if the results of the ...
Meta-analyses (MAs) began to spread in the mid-20th century to integrate and synthesize the results of an increasing number of studies in areas such as psychology and epidemiology (Aguinis et al., 2011c; Geyskens et al., 2009).Essentially, MAs aim at synthesizing the effect of interest by aggregating the estimations of a number of primary studies to estimate a global effect size (Cooper ...
Meta-Analysis. Meta-analysis is a statistical analysis where studies are evaluated together to gain an understanding of the magnitude of similarities and differences in the reported outcomes (Borenstein et al. 2009; Cooper 2016; Glass 1976, 2000).Building on the foundation of a narrative review, a typical meta-analysis will have several common features: transparency of the search strategy ...
Meta-analysis is a collection of statistical methods that integrates the results of a large number of studies to provide an aggregate summary of knowledge in a research domain (Littell et al., 2008). The advantage of meta-analysis over an individual study is in its higher power (i.e., sample size; Geyskens et al., 2009).
A systematic review is guided filtering and synthesis of all available evidence addressing a specific, focused research question, generally about a specific intervention or exposure. The use of standardized, systematic methods and pre-selected eligibility criteria reduce the risk of bias in identifying, selecting and analyzing relevant studies.
When a review is performed following predefined steps (ie, systematically) and its results are quantitatively analyzed, it is called meta-analysis. Publication of meta-analyses has increased exponentially in pubmed.gov; using the key word "meta-analysis, 1,473 titles. ". were yielded in 2007 and 176,704 on January 2020.
The goal of this study is to present a brief theoretical foundation, computational resources and workflow outline along with a working example for performing systematic or rapid reviews of basic research followed by meta-analysis. Conventional meta-analytic techniques are extended to accommodate methods and practices found in basic research.
This sort of circumstance would seem to call for a meta-analysis of the community level studies. 1 Acknowledging this point, some researchers have recently argued that meta-analyses of the case study literature should become an integral part of a 'portfolio' of approaches to the study of regional and global environmental change (Young et al ...
Meta-analysis would be used for the following purposes: To establish statistical significance with studies that have conflicting results. To develop a more correct estimate of effect magnitude. To provide a more complex analysis of harms, safety data, and benefits. To examine subgroups with individual numbers that are not statistically significant.
The case-control or respective cohort studies were evaluated using the Newcastle-Ottawa scale (NOS) to determine their techniqueological rigor.The Cochrane Collaboration's risk assessment tool was employed to perform quality evaluations for randomized controlled trials. ... Meta-analysis of these 9 studies showed that the rate of AD was ...
Sensitivity analysis is a common approach for examining the sources of heterogeneity on a case‐by‐case basis. 65 In sensitivity analysis, one or more studies are excluded at a time and the impact of removing each or several studies is evaluated on the summary results and the between‐study heterogeneity.
From 3221 records identified, 43 studies with 12,041 TB patients were finally included in the meta-analysis. Figure 1 depicts the process of identification, screening and inclusion of studies. The characteristics and quality of the 43 included studies are described in Table 1.A majority of studies (n = 30) had prospective cohort design, eight were case-control studies, while two were RCT and ...