Evaluation of the association between vitamin D and lung cancer skin metastasis

Abstract Background: This study aims to investigate the association between vitamin D (VD) and lung cancer skin metastasis (LCSM). Methods: The following databases will be retrieved from the beginning to the present of each database without language limitation: PUBMED, EMBASE, Cochrane Library, Web of Science, CBM, and CNKI. The reference lists of included trials and other sources will also be checked. Two researchers will independently undertake literature selection, data collection, and study quality evaluation. We will utilize a fixed or random-effect model to pool the data according to the heterogeneity test. The RevMan 5.3 software will be used to analyze the data and perform meta-analysis. Results: This study will summarize high quality study to explore the association between VD and LCSM. Conclusion: The findings of this study will help to judge whether there is association between VD and LCSM. Ethics and dissemination: No research ethical approval is required in this study, because it will only analyze published data. It is expected to disseminate through a peer-reviewed journal. Study registration: osf.io/ph2au.


Objective
This study protocol aims to investigate the association between VD and LCSM.

Study registration
This study has been registered on OSF (osf.io/ph2au). It is reported based on the guideline of Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol statement. [32] 2.3. Inclusion criteria for study selection 2.3.1. Type of studies. Case-controlled study (CCS) will be considered for inclusion in this study. Other types of studies will be excluded, such as animal study, case report, case series, and review.

2.3.2.
Type of participants. This study will include subjects who were diagnosed as LCSM or normal participants without restrictions to race, age, and sex. However, patients will be excluded if they had skin metastasis from other cancers, or skin cancer alone.
2.3.3. Type of exposures. This study will test serum levels of VD in patients with LCSM.

2.3.4.
Type of controls. This study will examine serum levels of VD in normal healthy participants.
2.3.5. Type of outcome measurements. Outcomes include levels of serum vitamin D, number of skin metastasis, disease progression rate, overall survival rate, mortality rate, and quality of life.

Search methods for the identification of studies
PubMed, EMBASE, Cochrane Library, Web of Science, CBM, and CNKI will be retrieved from the beginning to the present without language limitation. The search strategy sample for PubMed is demonstrated in Table 1. It will be modified by using other electronic databases. Additionally, the reference lists of included trials, conference papers related to the topic, and clinical trials registry will be searched to avoid missing potential studies.
2.5. Data collection and analysis 2.5.1. Selection of studies. All searched literature will be imported into Endnote X9.0 software, and duplicates will be excluded. Then, 2 researchers will independently scan the titles, abstracts, and full texts of potential citations to select included studies. The reasons for all excluded studies will be recorded in a table. Any confusion will be cleared up by consulting a third researcher. A flow chart will be utilized to present study selection process.
2.5.2. Data collection and management. Two researchers will independently extract necessary information from included studies. It consists of title, first author, year of publication, journal, location, patient demographics, types of exposures, outcome measurements, results/findings, limitations, conflict of interest, and funding information. We will consult a third researcher if there are divisions between 2 authors.

Study quality assessment.
The study quality of all included CCS will be evaluated using The Newcastle-Ottawa Scale. [33,34] All included studies will be graded as high, moderate, and low risk according to the criteria of this tool. Any discrepancy will be settled down by consensus between 2 researchers and an additional researcher.
2.5.4. Dealing with missing data. To obtain unclear or missing data, we will contact first or corresponding author to obtain it by email or telephone. If that fails, we will analyze the existing data using intention to treat analysis.
2.5.5. Assessment of heterogeneity. I 2 test will be used to assess statistical heterogeneity. I 2 50% is considered as low heterogeneity, and we will employ a fixed-effect model to pool the data. I 2 > 50% is considered as substantial heterogeneity, and we will use a random-effect to synthesize the data. Meanwhile, sensitivity or subgroup analysis will be performed to investigate the possible causes of heterogeneity.
2.5.6. Assessment of reporting biases. If sufficient number of included studies (over 10 studies) is entered, we will examine reporting bias using funnel plot and Egger regression test. [35] 2.5.7. Statistical analysis. RevMan 5.3 software will be employed for data synthesis. For dichotomous outcome data, risk ratio or odds ratio and 95% confidence intervals (CIs) will be used to calculate treatment effect. Mean difference (MD) or standardized MD and 95% CIs will be utilized to estimate treatment effect for continuous data. Whenever possible, we will carry out a meta-analysis if sufficient data are extracted on the same outcome with ample similarity in study information, patient demographics, details of exposures, and outcomes. If outcome data cannot be synthesized, and a meta-analysis cannot be performed, we will undertake descriptive analysis.

Subgroup analysis.
If it is necessary, we will carry out a subgroup analysis based on different types of study information, exposures, and outcomes.
2.5.9. Sensitivity analysis. We will conduct a sensitivity analysis to check the stability of combined outcome results according to sample size, methodological quality, and missing data.

Discussion
This study will firstly investigate the association between VD and LCSM. We will systematically and comprehensively search literature resources, including electronic databases and grey literature sources to avoid missing potential studies. Two researchers will independently conduct study selection, data extraction, and study quality assessment, respectively. Any confusion between 2 researchers will be solved by a third Table 1 Detailed search strategy of Cochrane Library.

Number
Search terms researcher through discussion, and a consensus will be reached after discussion. If it is possible, we will pool the data and carry out meta-analysis. If it is not possible to synthesize the data, we will report study findings by narrative description. The findings of this study will provide evidence to support the association between VD and LCSM.