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Systematic Review

Genome-wide association studies (GWAS) for orthopedic diseases: a systematic review

[version 1; peer review: 1 approved with reservations, 1 not approved]
PUBLISHED 30 Jan 2023
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This article is included in the Genomics and Genetics gateway.

Abstract

Background and Objective: The objective of this review is to examine genome-wide association studies (GWAS) and whether they have helped treat orthopedic diseases in general and in the Middle East in particular.
Methods: Between 2005 and May 2022, we searched MEDLINE, Scopus, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and the Science Citation Index. Our criteria for manuscript analysis included articles involving patients with the presence or absence of the gene and single nucleotide polymorphism (SNP) that were published in the English language. The exclusion criteria included review articles and correspondence. We reviewed all of the articles manually for risk of bias and found no discrepancies in the papers selected.
Results: There were 53,652 GWAS articles that reported on the Human Genome Project, out of which 439 studies reported on orthopedics. In total, 38 studies with data from 1,489,834 patients was analyzed.
Conclusions: We identified many novel loci that can cause disease processes. We expected these studies to help in predicting diseases and developing new diagnostic procedures, preventive strategies, and better clinical care; however, this has not happened yet. It appears that we must investigate further before translating this knowledge in patient care.

Keywords

Genome Wide Association Studies, Human Genome Project, Orthopedics, Middle East

Introduction

Johann Gregor Mendel (1822-1884) developed the concept of genes and inheritance through his work on pea plants (Roberts 1929). The inception of the Human Genome Project (HGP) was first put on paper in 1988 and aimed to map all human genes. It took over 30 years to complete and the final gapless assembly was finished in January 2022. The main goals of the HGP were to determine the correct sequence of 3 billion nucleotide that makes up the whole of human DNA and to find all human genes, sequence the entire genome, and eliminate disease-causing genes. Genome-wide association studies (GWAS) are blueprints that are used to link recognizable associations between genetic variants and diseases among the people, which could eventually predict the occurrence of diseases and identify ideal prevention strategies and treatment modalities. This has led to an increase in GWAS in many countries to identify heritable phenotypes and to institute therapeutic interventions (Uffelmann et al. 2021). To date, GWAS have been carried out on millions of people and have identified 40 diseases that are influenced by the genes they carry (Manolio et al. 2008).

Many GWAS have been carried out to find the genetic influence on orthopedic diseases that run in families, such as adolescent idiopathic scoliosis (AIS) (Kou et al. 2019; Man et al. 2019; Khanshour et al. 2018), developmental dysplasia of the hip (DDH) (Hatzikotoulas et al. 2018), osteoarthritis of the knee (OAK) (Zengini et al. 2018; Soul et al. 2018), osteoarthritis of the hip (OAH) (Styrkarsdottir et al. 2017; Evans et al. 2015), and osteoporosis-related fragility fractures (Guo et al. 2012). The objective of this review is to report the GWAS performed on all orthopedic diseases and to ascertain whether any preventive strategies and treatments were established and succeeded.

Methods

Between 2005 and May 2022, we searched in MEDLINE, Scopus, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and the Science Citation Index with the following key words: orthopedics, Human Genome Project, GWAS, target genes and clinical translation. We supplemented our searches by manually reviewing the bibliographies of eligible studies and relevant review articles. Keywords were used instead of full sentences or questions in multiple search boxes. The keywords were supplemented with synonyms combined by “OR” and all forms of a keywords were garnered by using an asterisk symbol (*) after the root of a keyword. The database search limits were for English Language only.

The inclusion criteria included studies involving patients that were published in the English language. The exclusion criteria included review articles and correspondence.

The data was retrieved to find out the number of studies performed, the specific diseases identified and the total number of subjects screened. We pooled the numbers of each disease studied and compared the diseases and number of subjects. Lastly, the data was meticulously searched for any recommended preventive strategies and suggestive treatments. All of the articles were reviewed by the author for risk of bias, who found no discrepancies in the papers selected because only the presence or absence of the gene and SNP was considered. This review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher et al. 2009; Sadat-Ali & Sadat-Ali 2022).

Results

There were 53,652 GWAS that reported on the Human Genome Project, out of which 439 studies reported on GWAS and orthopedics. After the inclusion and exclusion criteria were considered, 38 studies with data from 1,489,834 patients were analyzed (Figure 1). Table 1 displays the data from those 38 studies. In total, 21 orthopedic conditions were studied, with the majority being osteoarthritis (867,648), back pain (158,000), AIS (125,015), ligament injuries (102,979), bone mineral density (BMD) (64,765) and osteonecrosis of the femur head (60,217) (Figure 2). Overall, 18 countries were represented in the studies, with the United States of America (16), United Kingdom (14) and China (14) being the most common (Figure 3). Unfortunately, none of the studies were carried out in the Middle East. Based on the review, the GWAS were unable to predict any diseases but were able to help develop treatments for ankylosing spondylitis and osteoporosis.

16f26861-10e5-41d1-bbee-f0cd42eb3e11_figure1.gif

Figure 1. PRISMA flow chart of the review.

Table 1.

List of all published GWAS analyzed.

NoAuthorsTitleJournalDiseaseNo of patients
1.Kim SK, Roos TR, Roos AK, Kleimeyer JP, Ahmed MA, Goodlin GT et al. (2017)Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy.PLoS One. 2017 Mar 30;12(3):e0170422.ACL102979
2.Pei YF, Hu WZ, Yan MW, Li CW, Liu L, Yang XL, Hai R, Wang XY, Shen H, Tian Q, Deng HW, Zhang L. (2018)Joint study of two genome-wide association meta-analyses identified 20p12.1 and 20q13.33 for bone mineral density.Bone. 2018 May;110:378-385BMD32965
3.Wei J, Li M, Gao F, Zeng R, Liu G, Li K (2016)Multiple analyses of large-scale genome-wide association study highlight new risk pathways in lumbar spine bone mineral density.Oncotarget. 2016 May 24;7(21):31429-39Bone density31800
4.Suri P, Palmer MR, Tsepilov YA, Freidin MB, Boer CG, Yau MS et al. (2018)Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.PLoS Genet. 2018 Sep 27;14(9):e1007601Back Pain158000
5.Khanshour AM, Kidane YH, Kozlitina J, Cornelia R, Rafipay A, De Mello V et al. (2021)Genetic association and characterization of FSTL5 in isolated clubfoot.Hum Mol Genet. 2021 Jan 21;29(22):3717-3728CTEV399
6.Skuladottir AT, Bjornsdottir G, Ferkingstad E, Einarsson G, Stefansdottir L, Nawaz MS et al. (2022)A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.Nat Commun. 2022 Mar 24;13(1):1598CTS48843
7.Hatzikotoulas K, Roposch A; DDH Case Control Consortium, Shah KM, Clark MJ, Bratherton S et al. (2018)Genome-wide association study of developmental dysplasia of the hip identifies an association with GDF5.Commun Biol. 2018 May 31;1:56.DDH834
8.Hsu YH, Liu Y, Hannan MT, Maixner W, Smith SB, Diatchenko L et al. (2015)Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans.J Med Genet. 2015 Nov;52(11):762-9.Hallux Valgus4409
9.Arbeeva L, Yau M, Mitchell BD, Jackson RD, Ryan K, Golightly YM, Hannan MT, Nelson A, Jordan JM, Hochberg MC (2020)Genome-wide meta-analysis identified novel variant associated with hallux valgus in Caucasians.J Foot Ankle Res. 2020 Mar 4;13(1):11.Hallux Valgus2314
10.Kou I, Otomo N, Takeda K, Momozawa Y, Lu HF, Kubo M, et al. (2019)Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese.Nat Commun. 2019 Aug 15;10(1):3685Scoliosis79211
11.Man GC, Tang NL, Chan TF, Lam TP, Li JW, Ng BK, Zhu Z, Qiu Y, Cheng JC (2019)Replication Study for the Association of GWAS-associated Loci With Adolescent Idiopathic Scoliosis Susceptibility and Curve Progression in a Chinese Population.Spine (Phila Pa 1976). 2019 Apr 1;44(7):464-471Scoliosis319
12.Khanshour AM, Kou I, Fan Y, Einarsdottir E, Makki N, Kidane YH, et al. (2018)Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci.Hum Mol Genet. 2018 Nov 15;27(22):3986-3998.AIS33476
13.Zhu Z, Tang NL, Xu L, Qin X, Mao S, Song Y et al. (2015)Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls.Nat Commun. 2015 Sep 22;6:8355.AIS4317
14.Grauers A, Wang J, Einarsdottir E, Simony A, Danielsson A, Åkesson K et al. (2015)Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis.Spine J. 2015 Oct 1;15(10):2239-46.Scoliosis1739
15.Zhu Z, Xu L, Leung-Sang Tang N, Qin X, Feng Z, et al. (2017)Genome-wide association study identifies novel susceptible loci and highlights Wnt/beta-catenin pathway in the development of adolescent idiopathic scoliosis.Hum Mol Genet. 2017 Apr 15;26(8):1577-1583Scoliosis5953
16.Lin X, Li L, Liu X, Tian J, Zheng W, Li J, Wang L. (2020)Genome-wide analysis of aberrant methylation of enhancer DNA in human osteoarthritis.BMC Med Genomics. 2020 Jan 3;13(1):1. doi: 10.1186/s12920-019-0646-9.OA108
17.Panoutsopoulou K, Thiagarajah S, Zengini E, Day-Williams AG, Ramos YF, Meessen JM et al. (2017)Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis.Ann Rheum Dis. 2017 Jul;76(7):1199-1206OA Hip2118
18.Styrkarsdottir U, Helgason H, Sigurdsson A, Norddahl GL, Agustsdottir AB, Reynard LN et al. (2019)Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis.Nat Genet. 2017 May;49(5):801-805OA Hip4,657
19.Evans DS, Cailotto F, Parimi N, Valdes AM, Castaño-Betancourt MC, Liu Y et al. (2015)Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis.Ann Rheum Dis. 2015 Oct;74(10):1861-7.OA Hip654
20.Zengini E, Hatzikotoulas K, Tachmazidou I, Steinberg J, Hartwig FP, Southam L et al. (2018)Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis.Nat Genet. 2018 Apr;50(4):549-558.OA30729
21.Soul J, Dunn SL, Anand S, Serracino-Inglott F, Schwartz JM, Boot-Handford RP, Hardingham TE. (2018)Stratification of knee osteoarthritis: two major patient subgroups identified by genome-wide expression analysis of articular cartilage.Ann Rheum Dis. 2018 Mar;77(3):423.OA Knee2692
22.Boer, C.G. Konstantinos, H. Southam, L. Stefansdottir, L. Zhang,Y. de Almeida, R. C et al. (2021)Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.Cell. 2021 Sep 2;184(18):4784-4818OA826690
23.Sakamoto Y, Yamamoto T, Sugano N, Takahashi D, Watanabe T, Atsumi T et al. (2017)Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head.Sci Rep. 2017 Nov 8;7(1):15035.Osteonecrosis Hip60000
24.Baek SH, Kim KI, Yoon KS, Kim TH, Kim SY. (2017)Genome-wide association scans for idiopathic osteonecrosis of the femoral head in a Korean population.Mol Med Rep. 2017 Feb;15(2):750-758Osteonecrosis Hip217
25.Koster R, Panagiotou OA, Wheeler WA, Karlins E, Gastier-Foster JM, Caminada de Toledo SR et al. (2018)Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patientsInt J Cancer. 2018 Apr 15;142(8):1594-1601Osteosarcoma523
26.Mirabello L, Koster R, Moriarity BS, Spector LG, Meltzer PS, Gary J et al. (2015)A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with OsteosarcomaCancer Discov. 2015 Sep;5(9):920-31Osteosarcoma935
27.Rangkasenee N, Murani E, Brunner RM, Schellander K, Cinar MU, Luther H, et al. (2013)Genome-Wide Association Identifies TBX5 as Candidate Gene for Osteochondrosis Providing a Functional Link to Cartilage Perfusion as Initial Factor.Front Genet. 2013 May 10;4:78.Osteochondrosis298
28.Guo Y, Wang JT, Liu H, Li M, Yang TL, Zhang XW, Liu YZ, Tian Q, Deng HW (2012)Are bone mineral density loci associated with hip osteoporotic fractures? A validation study on previously reported genome-wide association loci in a Chinese population.Genet Mol Res. 2012 Jan 31;11(1):202-10.Osteoporotic Hip fractures350
29.Kim SK, Nguyen C, Horton BH, Avins AL, Abrams GD (2021c)Association of COA1 with Patellar Tendonitis: A Genome-wide Association Analysis.Med Sci Sports Exerc. 2021 Nov 1;53(11):2419-2424Patellar Tendonitis1670
30.Roos TR, Roos AK, Avins AL, Ahmed MA, Kleimeyer JP, Fredericson M et al. (2017)Genome-wide association study identifies a locus associated with rotator cuff injury.PLoS One. 2017 Dec 11;12(12):e0189317.Rotator Cuff8357
31.Tashjian RZ, Granger EK, Farnham JM, Cannon-Albright LA, Teerlink CC (2016)Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms.J Shoulder Elbow Surg. 2016 Feb;25(2):174-9.Rotator Cuff2641
32.Kim SK, Nguyen C, Jones KB, Tashjian RZ. (2021a)A genome-wide association study for shoulder impingement and rotator cuff disease.J Shoulder Elbow Surg. 2021 Sep;30(9):2134-2145rotator cuff disease.3864
33.Jiang H, Moro A, Liu Y, Wang J, Meng D, Zhan X, Wei Q. (2020)Two GWAS-identified variants are associated with lumbar spinal stenosis and Gasdermin-C expression in Chinese population.Sci Rep. 2020 Dec 3;10(1):21069Stenosis400
34.Cheung JPY, Kao PYP, Sham P, Cheah KSE, Chan D, Cheung KMC, Samartzis D (2018)Etiology of developmental spinal stenosis: A genome-wide association study.J Orthop Res. 2018 Apr;36(4):1262-1268Spinal stenosis469
35.Nakajima M, Takahashi A, Tsuji T, Karasugi T, Baba H, Uchida K et al. (2014)A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine.Nat Genet. 2014 Sep;46(9):1012-6.Spine8000
36.Kim SK, Nguyen C, Avins AL, Abrams GD. (2021b)Identification of Three Loci Associated with Achilles Tendon Injury Risk from a Genome-wide Association Study.Med Sci Sports Exerc. 2021 Aug 1;53(8):1748-1755TA Injury12,354
37.Sood RF, Westenberg RF, Winograd JM, Eberlin KR, Chen NC (2020)Genetic Risk of Trigger Finger: Results of a Genomewide Association Study.Plast Reconstr Surg. 2020 Aug;146(2):165e-176eTrigger Finger942
38.Styrkarsdottir U, Stefansson OA, Gunnarsdottir K, Thorleifsson G, Lund SH, Stefansdottir L et al (2019)GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures.Nat Commun. 2019 May 3;10(1):2054. doi: 10.1038/s41467-019-09860-0.Height + BMD + OA13608
16f26861-10e5-41d1-bbee-f0cd42eb3e11_figure2.gif

Figure 2. Diseases and number of patients studied in GWAS.

16f26861-10e5-41d1-bbee-f0cd42eb3e11_figure3.gif

Figure 3. Countries participated in GWAS.

Discussion

This review shows that the Human Genome Project and GWAS have done tremendous work in genetic mapping many diseases in general and a few common orthopedic diseases. The GWAS on osteoarthritis (OA), which affects more than 300 million people around the world, has some positive findings and identifies 100 independently associated risk variations, out of which 52 were not described or known to be associated with OA (Boer et al. 2021). The other sites of osteoarthritis, such as the hip and knee, were also studied (Soul et al. 2018; Styrkarsdottir et al. 2017; Evans et al. 2015; Panoutsopoulou et al. 2017). Osteoarthritis of the knee (OAK) was reported to be common in over 53% of men and 60.9% of women in Saudi Arabian populations and has continued to increase. In 2011, funding was requested by the author but not awarded to assess the association between genetic polymorphisms and OA among Saudi Arabian men and women. (Al-Omran, Sadat-Ali and AlHammam 2011).

AIS was the second most common disease that the GWAS found was genetically influenced. It affects 0.47-5.2% of healthy children and during growth spurts, the curves increase (Konieczny et al. 2013). Overall, 25 different loci were identified in a variety of ethnic groups (Kou et al. 2019; Man et al. 2019; Khanshour et al. 2018; Zhu et al. 2015; Grauers et al. 2015). Further sub group analysis highlighted two SNPs (rs1190870 and rs678741) that were significantly associated with the presence of right thoracic curves (Man et al. 2019). None of the studies were conducted on Middle Eastern populations, even though a target gene and three SNPs were identified for AIS in the Saudi Arabian population (Sadat-Ali et al. 2011; Al-Othman et al. 2017). In the Middle East, most female children remain covered from the neck down, allowing the AIS to remain undetected until it’s too late. A clinical translation of the GWAS could promote early diagnosis of AIS and prevent surgery that causes tremendous morbidity.

Developmental dysplasia of the hip (DDH) was another disease that the GWAS examined. Hatzikotoulas et al. (2018) performed a GWAS on DDH in the United Kingdom and reported that there is strong genetic association locus at GDF5 (rs143384). At the same time, the author and his associates in Saudi Arabia conducted a study with 473 subjects (100 patients, 200 parents, 73 siblings and 100 healthy controls) (Sadat-Ali et al. 2018) and reported that there was a definite relationship between GDF5 (SNP rs143383) and DDH. For the first time, it was found that the genotype TT and the T allele were overly expressed in the patients and the fathers. In the United Kingdom, it was reported that 1-2 babies out of 1000 require DDH treatment (https://www.nhs.uk/conditions/developmental-dysplasia-of-the-hip/). A recent meta-analysis found that in Saudi Arabia, incidence of DDH was 10.46 out of 1000, and in over 40% of patients was the result of family history. The meta-analysis found an average of 22,336 cases at any given time in the country with 7,119 new cases added yearly (Sadat-Ali 2020). Many cases of DDH are clustered in specific towns and cities. If the GWAS can be clinically translated, early diagnosis will provide clinically beneficial improvements in patient care and ensure that children can have non-surgical DDH treatment, which could limit the long term morbidity and complications of surgical treatments.

The other diseases that GWAS showed were genetically influenced and common in clinical practice included back pain, ligament injuries, osteonecrosis of femur heads and osteoporosis related issues. Clinical translation based on GWAS could improve prediction and progression for some diseases. These studies could identify therapeutic targets leading to therapeutic agents. Unfortunately, even after screening over a million patients, the benefits in drug discovery were inappreciable. From an orthopedic surgeon’s perspective, GWAS linked two genes that were identified as RANKL/ESR1 and TNFR1/PTGER4/TYK2. The former allowed drugs like denosumab, a potent antiresorptive, to be developed, whereas the other allowed fostamatinib to be developed for ankylosing spondylitis (Schwarz and Ritchlin 2007; Tak and Kalden 2011).

On the aspect of disease prediction, ScolioscoreTM is supposed to identify patients whose curve will progress in AIS (Visscher et al. 2017). Unfortunately, the independent validation could not confirm this (Carlson 2011).

Our study has certain limitations. First, we did not discuss all of the orthopedics diseases reported in the GWAS in this review in detail. Second, the review showed that a limited number of diagnostic procedures could predict the diseases based on the GWAS studies. Moreover, the ScolioscoreTM that could predict the progression of curves in AIS that came out of these studies still needs to be independently validated. Compared to the rest of the world, GWAS in Middle Eastern countries are so low that the magnitude of reports is markedly incomparable (99.99 to 0.01%) (Suri et al. 2018).

In conclusion, HAP and GWAS have produced and identified many novel loci that can cause disease processes. Many more studies are being conducted to find new loci and genetic ancestries and these studies were expected to help predict diseases and develop new diagnostic methods, preventive strategies and better clinical care, but this has not happened yet. Our review showed that a limited number of drugs came into existence based on the GWAS studies. One test that could predict the progression of curves in AIS came out of these studies, but it still needs to be independently validated. It appears that we must continue investigating instead of translating this knowledge to improve patient care.

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Sadat-Ali M. Genome-wide association studies (GWAS) for orthopedic diseases: a systematic review [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:113 (https://doi.org/10.12688/f1000research.126829.1)
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
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PUBLISHED 30 Jan 2023
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Reviewer Report 18 Sep 2023
Serra Kaya, University of California San Francisco, San Francisco, California, USA 
Approved with Reservations
VIEWS 5
In this systematic review paper, the author's primary objective was to identify genome-wide association studies (GWAS) related to orthopedic diseases published worldwide within the years 2005-2022, with a specific focus on the Middle East. He concluded that out of 53,652 ... Continue reading
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Kaya S. Reviewer Report For: Genome-wide association studies (GWAS) for orthopedic diseases: a systematic review [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:113 (https://doi.org/10.5256/f1000research.139277.r193284)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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5
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Reviewer Report 29 Aug 2023
Mehdi Momen, University of Wisconsin-Madison, Madison, Wisconsin, USA 
Not Approved
VIEWS 5
This paper aims to evaluate the impact of genome-wide association studies (GWAS) on understanding and treating orthopedic diseases, particularly in the context of the Middle East. The study collected and analyzed GWAS articles related to orthopedic diseases between 2005 and ... Continue reading
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HOW TO CITE THIS REPORT
Momen M. Reviewer Report For: Genome-wide association studies (GWAS) for orthopedic diseases: a systematic review [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:113 (https://doi.org/10.5256/f1000research.139277.r187936)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (0)

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Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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