Protocol for a Systematic Review of Outcome Measurement Tools for Autologous fat Grafting of the Facial Region

Abstract

systematic review aims to critically evaluate the current available outcome measurement methods, and compare them with regards to accuracy, cost-effectiveness, safety and validation in the clinical setting.
The quality of evidence of included publications will be assessed using the GRADE strategy.

Methods
A comprehensive, structured literature search of published articles will be conducted. This is designed by authors and performed in adherence to the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA-P). The literature search will be performed using the electronic databases MEDLINE (PubMed), EMBASE and Cochrane Library, including publications from inception to May 2020. Two independent authors will conduct the search, screen the articles, and complete data collection. The main outcome will be which methods are currently used to determine a successful fat grafting procedure in the face. We propose to review the current methods used to establish their overall performance in several domains. In addition, patients measured via the 3D volumetric photography method will be further analysed with regards to accuracy of the camera and retention of fat per method and ml injected.

Discussion
Autologous fat grafting in the facial region has gained signi cant attention in the eld of plastic and reconstructive surgery in the past decades. In light of the growing public interest in this topic, a systematic review of the outcome measurement tools is of essence. We will critically evaluate all approaches currently in practice and give a recommendation regarding several aspects of use. A common approach to measurement and reporting of results fosters an environment of high-standard healthcare delivery and promotes future research and informed clinical practice. In addition, we will further analyse the outcomes of different grafting methods using 3D volumetric photography as measurement tool.

PROSPERO registration number: CRD42020213407
Page 3/10 Background Autologous fat grafting (AFG) has become an established method in the eld of plastic-reconstructive surgery over the past two decades. Since the beginning of structural fat grafting, where Coleman et al.
(1-3) rst described a standardised method which is still broadly in use today, different types of harvesting, processing and grafting methods have emerged. In addition to that, the lipoaspirate can be used in combination with other biological products. These include cell assisted lipo lling (CAL), where fat is combined with adipose-derived stem cells (ADSC) which have been reported to improve fat survival rate (4), ADSC transfer only, fat plus stromal vascular fraction (SVF) transfer, which contains ADSC's, endothelial cells, endothelial progenitor cells, pericytes, preadipocytes and hematopoietic cells (5) and fat plus platelet rich plasma (PRP), which is claimed to support angiogenesis and reduce absorption of fat (6,7). Popular measurement methods include subjective parameters such as patient satisfaction surveys, and scores given by a jury voting on pre-and postoperative photographs.
Objective methods include volumetric measurements via 3D-photography, magnetic resonance imaging or computed tomography. In the aesthetic eld common parameters include skin quality, more speci cally skin texture, skin colour, elasticity and histological outcomes. (9) The purpose of this systematic review is to better understand and compare the objective and subjective outcome measurement tools currently used following fat grafting in the facial region and to propose a core of outcome set (COS) to be used in facial fat grafting. This will help create reproducible studies and experiments and comparability of outcomes. A more detailed analysis of the studies using 3D volumetric photography as outcome measurement method will be undertaken. In addition, grafting methods CAL, ADSC only, SVF enriched graft and fat only will be compared where primary empirical evidence exists.

Methods
This protocol has been submitted to the PROSPERO database and is currently under review for registration (ID: 213407). A comprehensive, structured literature search of published articles will be conducted. This is designed by authors S.S. B.L. and A.A., and performed in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA-P) (10).

Search Strategy
The literature search will be performed using the electronic databases MEDLINE (PubMed), EMBASE and Cochrane Library, including publications from inception to May 2020. The keywords used in the search will be selected from key papers and are described in Table 1. Search strings 1 and 2 will be combined using the Boolean term AND, then the limits are applied. Furthermore, a 'MeSH term' search will be conducted, and the reference lists of included articles are reviewed for any additional articles. The full search strategy is provided in the appendix. Study selection will be independently assessed by 2 reviewers (S.S. and B.L.), any persisting disagreements were reviewed and adjudicated by a third reviewer (A.A.). Table 1 Number Search terms String 1 "Fat graft" or "Fat grafting" or "Fat transplant" or "Fat transplantation" or "Fat transfer" or "Fat augmentation" or "Fat injection" or "Lipoinjection" or "Lipotransfer" or "Lipo lling" or "Lipograft" or "Autologous fat" or "Autogenous fat" or "lipoaspirate" or "nanofat" or "microfat" String 2 "face" or "facial" or "midface" or "head and neck" or "maxillofacial" or "facial reconstructive" or "facial asymmetry" or "facial hemiatrophy" or "lipodystrophy" or "facelift" or "rhytidectomy" or "facial rejuvenation" or "rhinoplasty" or "cheek" or "eyelid" or "nose" or "forehead" or "glabella" or "chin" or "nasolabial" or "buccal" or "periocular" or "periorbital" or "mouth"

Study selection criteria
Articles are eligible for inclusion if they provide primary empirical evidence of patient outcomes after fat grafting. Outcome measures reported are categorized as either objective or subjective and reported separately. The full inclusion and exclusion criteria are detailed in Table 2. Inclusion: Patients of any age and any gender, regardless of ethnicity, who have undergone autologous fat grafting (AFG) to the facial region one or several times. This can be out of various reasons including but not limited to: reconstructive purposes such as reduction of defects and asymmetries after head and neck cancer surgery, congenital maxillofacial de cits and aesthetic indications including lipo lling for facial rejuvenation.
Exclusion: Patients who have undergone AFG in any other region than the face, or where no outcomes are reported.

Outcome
The main outcome will be which methods are currently used to determine a successful fat grafting procedure in the face. We will then compare these methods regarding accuracy, cost-effectiveness, safety and validation in the clinical setting. The accuracy will be analysed by comparison of ml of injected fat to measurement of pre-to postoperative and long-term follow up outcomes.
The cost effectiveness will be evaluated by comparison of cost of acquisition of machine divided by number of measurements achieved by this machine.
The safety will be measured by adverse events.
The tools will also be rated by status of validation (validated y/n) In addition, we will analyse -amount of fat injected by facial subunit in ml -the subset of patients measured via volumetric methods will be further analysed with regards to retention of fat per method and ml injected. Articles are scanned, analysed and data extracted using a predesigned data collection sheet. This data collection template is tested in two randomly chosen publications, before being used on all included articles. Data extracted include patient demographics (gender, age, comorbidities), the details of the fat grafting protocol used (donor site, processing methodology, graft volume) and any outcome measures reported including time to outcome measurement and any complications.

Subgroup analyses
Assuming that su ciently robust patient groups can be identi ed from the studies, the different fat grafting methods and patient aetiologies (reconstructive/aesthetic) will be considered separately.
Methodological Quality and risk of bias assessment Included studies are assigned a level of evidence based on the Oxford Centre for Evidence Based Medicine (11). In addition, randomized control trials are rated for bias using the GRADE approach. This includes the RoB version 2.0 tool for RCTs and ROBINS-I for Comparative studies (12).

Data analysis and synthesis
Data are analysed using IBM SPSS statistics version 24. Primary and secondary outcome measures will be evaluated using simple descriptive statistics. Where appropriate, we will provide pooled estimates with corresponding measures of dispersion.
We will only perform a meta-analysis if a su cient number of studies (minimum ≥ 3) with consistent characteristics are included. In the rst instance, we will combine all AFG techniques into a single intervention group. If ≥ 3 comparable studies are available for one or more intervention subtypes (namely lipotransfer, CAL, SVF-or ADSC-only), we will perform individual subgroup meta-analyses to statistically evaluate how these techniques compare to one another regarding the fat retention rate.
We will explore all sources of potential heterogeneity related to study design, participants, interventions, comparators and outcomes. Statistical heterogeneity will be assessed using the χ² test and quanti ed with the I² statistic. The thresholds for interpretation of the I² value will be in accordance with those presented in the Cochrane Handbook for Systematic Reviews of Interventions. An evaluation of between study heterogeneity will inform our decision as to whether a xed or random effects model is more appropriate for the dataset. If su cient studies are included in the meta-analysis, we will interrogate the accuracy of our overall outcome estimate using a sensitivity analysis.
Continuous outcomes will be analysed using either mean differences or standardised mean differences (with 95% con dence intervals (CIs)); dichotomous data will be analysed using risk ratios (with 95% CIs); time-to-event data will be analysed using hazard ratios (with 95% CIs).
In the event that a meta-analysis is not appropriate, we will combine the results of all included studies in a qualitative synthesis with reference to our primary and secondary outcomes. In this narrative evaluation, we will comment on whether the e cacy and safety of AFG outcome measurement methods appear to vary according to the intervention subgroups de ned above.

Discussion
Autologous fat grafting in the facial region has gained signi cant attention in the eld of plastic and reconstructive surgery in the past decades. Up to today, there is no single best measurement method of practice to determine a successful outcome of AFG to the face. In light of the growing public interest in this topic, a systematic review of the outcome measurement tools is of essence. We will critically evaluate all approaches currently in practice and give a recommendation regarding several aspects of use. In addition, we will further analyse the outcomes of different grafting methods using 3D volumetric photography as measurement tool. We hope to identify the most effective method with regards to accuracy of the camera and retention of fat per method and ml injected. Should one tool be observed to have the highest ratings in all domains tested, we will give a recommendation for future use. We also hope to identify which grafting technique is superior and whether this varies according to facial subunit injected or time to follow-up. Combined, we hope the conclusions will help shape the clinical decisionmaking process with aspects of nding the ideal transplantation technique for their patient and validating a successful result. We will discuss the generalisability and robustness of our results in light of the level of evidence and overall risk of bias of each summary outcome measure observed. A common approach to measurement and reporting of results fosters an environment of high-standard healthcare delivery and promotes future research and informed clinical practice.