The joys of sharing: andrology trailblazes in data transparency- an example using the World Health Organization 2021 reference ranges

In a concerted effort to improve reproducibility and reliability in science there is a tsunami of activity from journals, funders, scientists, and governments. The context is the plethora of studies continually showing scientific studies are not repeatable (Rodgers and Collings, 2021Rodgers P Collings A What have we learned?.Elife. 2021; 10: e75830https://doi.org/10.7554/eLife.75830Crossref PubMed Scopus (11) Google Scholar). This is damaging to the discipline(s), wasteful of valuable resources and undermines public confidence. The tsunami encompasses a wide spectrum of measures. For example, scientific journals providing detailed instructions on transparent reporting of research, such as the Cell Press STAR Methods format (Structure, Transparent, Accessible Reporting; https://www.cell.com/star-authors-guide), and increasing use of checklists detailing methods, materials and statistics. New initiatives such as the MDAR (Materials Design Analysis Reporting) Framework for transparent reporting (Macleod et al., 2021Macleod M Collings AM Graf C Kiermer V Mellor D Swaminathan S Sweet D Vinson V The MDAR (Materials Design Analysis Reporting) Framework for transparent reporting in the life sciences.Proc Natl Acad Sci U S A. 2021; 118e2103238118Crossref PubMed Scopus (25) Google Scholar) and the Open Science Framework (www.osf.io) are all designed to provide systems to improved reproducibility. Furthermore, to encourage rigour and replication, several journals are specifically targeting reproducibility studies. Nature has announced publication of a new type of research paper ‘Registered Reports’ (Nature editorial, 23 February 2023, https://doi.org/10.1038/d41586-023-00506-2). Suffice it to say, the collective objective of these measures is to substantially improve the quality of science. The direction of travel is clear. So, where does andrology stand? Vasconcelos and colleagues suggested, in this journal, a positive state of play (Vasconcelos et al., 2022Vasconcelos A Henedi Z Barratt CLR. WHO 2021 and 2030 reference values for semen assessment: three challenges for andrology in the journey ahead.Reprod Biomed Online. 2022; 45: 187-190Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). The World Health Organization (WHO) have produced a 6th edition of their laboratory manual for the examination and processing of human semen (WHO6) (World Health Organization 2021World Health OrganizationWHO Laboratory Manual for the Examination and Processing of Human Semen.6th edition. World Health Organization, Geneva2021Google Scholar) which has simple-to-follow and proven high-quality methods. Concurrently, the International Standards Organization (ISO) released ISO 2021ISOInternational Standards Organization. ISO 23162:2021 Basic semen examination — Specification and test methods. ISO, Geneva2021Google Scholar (Basic semen examination — Specification and test methods, https://www.iso.org/standard/74800.html) with procedures based on WHO6. Documents from both ISO and WHO will act in concert to facilitate robust data collection. Furthermore, a consortium of 86 authors produced a revised checklist for journals, authors, and referees to assess the quality of semen assessment methods (Björndahl et al., 2022Björndahl L Barratt CLR Mortimer D Agarwal A Aitken RJ Alvarez JG Aneck-Hahn N Arver S Baldi E Bassas L Boitrelle F Bornman R Carrell DT Castilla JA Cerezo Parra G Check JH Cuasnicu PS Darney SP de Jager C De Jonge CJ Drevet JR Drobnis EZ Du Plessis SS Eisenberg ML Esteves SC Evgeni EA Ferlin A Garrido N Giwercman A Goovaerts IGF Haugen TB Henkel R Henningsohn L Hofmann MC Hotaling JM Jedrzejczak P Jouannet P Jørgensen N Kirkman Brown JC Krausz C Kurpisz M Kvist U Lamb DJ Levine H Loveland KL McLachlan RI Mahran A Maree L Martins da Silva S Mbizvo MT Meinhardt A Menkveld R Mortimer ST Moskovtsev S Muller CH Munuce MJ Muratori M Niederberger C O'Flaherty C Oliva R Ombelet W Pacey AA Palladino MA Ramasamy R Ramos L Rives N Roldan ER Rothmann S Sakkas D Salonia A Sánchez-Pozo MC Sapiro R Schlatt S Schlegel PN Schuppe HC Shah R Skakkebæk NE Teerds K Toskin I Tournaye H Turek PJ van der Horst G Vazquez-Levin M Wang C Wetzels A Zeginiadou T Zini A Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology.Hum Reprod. 2022; 37: 2497-2502Crossref PubMed Scopus (5) Google Scholar). At the core of the reproducibility discussion is data transparency. What I mean by this is being able to access, on an open platform, the primary data underlying published studies. This is receiving increasing attention, brought into focus by the recent announcement from the National Institutes of Health (NIH) in the US that, by 2025, there will be a requirement for data sharing to encompass research across all scientific disciplines that receive federal funding (https://sharing.nih.gov/data-management-and-sharing-policy/about-data-management-and-sharing-policies/data-management-and-sharing-policy-overview). Effectively, this means data will need to be shared in public repositories, an approach consistent with other agencies (e.g., Bill & Melinda Gates Foundation). There are increasing appeals for data transparency across disciplines. A topical example is the large language model (LLM) of artificial intelligence where the need for freely available access to the primary data deriving the models is believed necessary for reproducibility (Spirling, 2023Spirling A. Why open-source generative AI models are an ethical way forward for science.Nature. 2023; 616: 413Crossref PubMed Scopus (5) Google Scholar). Depositing primary data in public repositories has been standard practice for some time in many areas such as proteomics and X-ray crystallography. In our own field we have seen real-world advantages from independent analysis of large publicly available data sets, such as that of the UK's Human Fertilisation and Embryology Authority (HFEA, https://www.hfea.gov.uk/about-us/data-research/), helping to guide clinical practice (e.g. Allen et al., 2023Allen C McLernon D Bhattacharya S Maheshwari A. Early pregnancy outcomes of IVF cycles using donor versus partner sperm: analysis of 1 376 454 cycles recorded by the Human Fertilisation and Embryology Authority (1991-2016).Hum Reprod. 2023 Mar 24; : dead057https://doi.org/10.1093/humrep/dead057Crossref PubMed Scopus (1) Google Scholar). How does andrology score on the data transparency scale? Well, there is work to be done but we have a sentinel example with the formulation of the World Health Organization 2021World Health OrganizationWHO Laboratory Manual for the Examination and Processing of Human Semen.6th edition. World Health Organization, Geneva2021Google Scholar reference ranges (Campbell et al., 2021Campbell MJ Lotti F Baldi E Schlatt S Festin MPR Björndahl L Toskin I Barratt CLR Distribution of semen examination results 2020 - A follow up of data collated for the WHO semen analysis manual 2010.Andrology. 2021; 9: 817-822Crossref PubMed Scopus (36) Google Scholar). From the outset, the objective of the WHO panel was to make all the primary data freely available on an open-source site (Campbell et al., 2021Campbell MJ Lotti F Baldi E Schlatt S Festin MPR Björndahl L Toskin I Barratt CLR Distribution of semen examination results 2020 - A follow up of data collated for the WHO semen analysis manual 2010.Andrology. 2021; 9: 817-822Crossref PubMed Scopus (36) Google Scholar; Barratt et al., 2022Barratt CLR Wang C Baldi E Toskin I Kiarie J Lamb DJ other Editorial Board Members of the WHO Laboratory Manual for the Examination and Processing of Human SemenWhat advances may the future bring to the diagnosis, treatment, and care of male sexual and reproductive health?.Fertil Steril. 2022; 117 (2022): 258-267Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar) so it could be added to and reanalysed, as and when appropriate (https://doi.org/10.15132/10000163). As one marker of its success, at the time of writing (April 2023) this information set has been downloaded in over 44 countries. It was originally anticipated that further data from studies on fertile men would be added, providing higher n values and more robust information (Campbell et al., 2021Campbell MJ Lotti F Baldi E Schlatt S Festin MPR Björndahl L Toskin I Barratt CLR Distribution of semen examination results 2020 - A follow up of data collated for the WHO semen analysis manual 2010.Andrology. 2021; 9: 817-822Crossref PubMed Scopus (36) Google Scholar). This takes time, but what has been encouraging is that several studies have already reassessed the current data for a variety of purposes, e.g., examination of geographical variation, global decline in sperm counts (Table 1). This exemplifies the power of making data freely accessible. Moreover, whilst not published yet, the data is being used for identifying guidelines for semen profiles for non-hormonal male contraceptive trials (guides for hormonal contraception already exist). Furthermore, companies, such as those developing male fertility testing, use it to present regulatory authorities with required information on the distribution of semen parameter data in fertile men. Although many of these uses were not originally anticipated, they are nevertheless welcome.Table 1Examples of studies using primary data used to compile the World Health Organization 2021World Health OrganizationWHO Laboratory Manual for the Examination and Processing of Human Semen.6th edition. World Health Organization, Geneva2021Google Scholar reference valuesStudyPurpose of data analysisPrimary conclusionFeferkorn et al., 2022aFeferkorn I Azani L Kadour-Peero E Hizkiyahu R Shrem G Salmon-Divon M Dahan MH. Geographic variation in semen parameters from data used for the World Health Organization semen analysis reference ranges.Fertil Steril. 2022; 118: 475-482Abstract Full Text Full Text PDF PubMed Scopus (5) Google ScholarExamine geographical variations in 2021 reference ranges.Significant geographic differences exist. Regional reference ranges based on local experience and treatment outcomes should be considered.Feferkorn et al., 2022bFeferkorn I Azani L Kadour-Peero E Hizkiyahu R Shrem G Salmon-Divon M Dahan MH. An evaluation of changes over time in the semen parameters data used for the World Health Organization semen analysis reference ranges.Andrology. 2022; 10: 660-668Crossref PubMed Scopus (3) Google ScholarExamine temporal trends in semen assessment.Although there were several significant differences in semen characterises over a three-decade period, these differences were not clinically significant.Paffoni et al., 2022Paffoni A Somigliana E Boeri L Viganò P. The statistical foundation of the reference population for semen analysis included in the sixth edition of the WHO manual: a critical reappraisal of the evidence.Hum Reprod. 2022; 37: 2237-2245Crossref PubMed Scopus (1) Google ScholarStatistical re-assessment of the reference ranges.There were significant differences between values in the various studies used to compile the reference ranges. Future studies should be prospective to increase applicability. Open table in a new tab There are challenges to sharing data on publicly available repositories, including the need for common platforms and standards, ethics, and additional costs preparing the data, to name a few (Federer, 2022Federer LM. Long-term availability of data associated with articles in PLOS ONE.PLoS One. 2022; 17e0272845Crossref PubMed Scopus (3) Google Scholar), but there are well-worked solutions (Kaiser and Brainard, 2023Kaiser J Brainard J.Ready set, share!.Science. 2023; 379: 322-325Crossref PubMed Scopus (3) Google Scholar; Hutson, 2022Hutson M. Taking the pain out of data sharing.Nature. 2022; 610: 220-221Crossref PubMed Scopus (3) Google Scholar). Interestingly, journals are responding to the requirement to supply primary information with publications in keeping with the FAIR (findable, accessible, interoperable, reusable) data principles. For example, Science (and its accompanying stable) will now partner with Dryad to help make data available and will cover the cost of facilitating this (Holden et al. (2023)Thorp H.Holden Vinson Valda Yeston Jake Strengthening the scientific record.Science. 2023; 380: 13Crossref PubMed Scopus (2) Google Scholar). This strategy is consistent with level II of the TOP Guidelines (Transparency and Openness Promotion; Centre for Open Science https://osf.io/9f6gx/wiki/Guidelines/). On the scale of things, the WHO reference range data is small. However, it provides an example of the positive value that arises from public repositories. Let's imagine for a moment this being expanded to other studies. Even if we restrict our horizon of thought to open data from semen analysis studies published over the last 12 months this would encompass tens of thousands of semen assessments from sub-fertile men (e.g., n = ∼22,000 Villani et al., 2022Villani MT Morini D Spaggiari G Falbo AI Melli B La Sala GB Romeo M Simoni M Aguzzoli L Santi D Are sperm parameters able to predict the success of assisted reproductive technology? A retrospective analysis of over 22,000 assisted reproductive technology cycles.Andrology. 2022; 10: 310-321Crossref PubMed Scopus (18) Google Scholar; n = ∼17,000 Akang et al., 2023Akang EN, Opuwari CS, Enyioma-Alozie S, Moungala LW, Amatu TE, Wada I, Ogbeche RO, Ajayi OO, Aderonmu MM, Shote OB, Akinola LA, Ashiru OA, Henkel R. Trends in semen parameters of infertile men in South Africa and Nigeria. Sci Rep. 2023 Apr 26;13(1):6819. https://doi.org/10.1038/s41598-023-33648-4.Google Scholar) let alone the multitude of data from analyses of trends in sperm count (Levine et al., 2023Levine H Jørgensen N Martino-Andrade A Mendiola J Weksler-Derri D Jolles M Pinotti R Swan SH. Temporal trends in sperm count: a systematic review and meta-regression analysis of samples collected globally in the 20th and 21st centuries.Hum Reprod Update. 2023; 29: 157-176Crossref PubMed Google Scholar). What a tremendously rich resource this would be. Inevitably, discussions about reliability and reproducibility will become more vociferous (Mol and Ioannidis, 2023 Feb 24Mol BW Ioannidis JPA. How do we increase the trustworthiness of medical publications?.Fertil Steril. 2023 Feb 24; (S0015-0282(23)00152-8)Abstract Full Text Full Text PDF Scopus (1) Google Scholar). The reality is that we all need data management plans, including a strategy of how to share primary data. Andrology has a good platform, and the World Health Organization 2021World Health OrganizationWHO Laboratory Manual for the Examination and Processing of Human Semen.6th edition. World Health Organization, Geneva2021Google Scholar reference ranges provide an example of the rewards, and the joys, of sharing. In this paper I use the term 'reference ranges' for simplicity. It is as defined in the fifth edition of the WHO manual (5th centile lower reference limits) (World Health Organization 2010World Health OrganizationWHO Laboratory Manual for the Examination and Processing of Human Semen.5th edition. World Health Organization, Geneva2010Google Scholar). There have been various terms used in the different editions of the manual. In the sixth edition (World Health Organization 2021World Health OrganizationWHO Laboratory Manual for the Examination and Processing of Human Semen.6th edition. World Health Organization, Geneva2021Google Scholar) the term used is 'distribution of semen variables of fertile men' (see Table 2 in Wang et al., 2022Wang C Mbizvo M Festin MP Björndahl L Toskin I other Editorial Board Members of the WHO Laboratory Manual for the Examination and Processing of Human SemenEvolution of the WHO "Semen" processing manual from the first (1980) to the sixth edition (2021).Fertil Steril. 2022; 117 (2022): 237-245Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar).