A Bayesian Reanalysis of the Overall and Sex-Disaggregated Results of the Neonatal Oxygenation Prospective Meta-Analysis (NeOProM)
Round 1
Reviewer 1 Report
Title: A Bayesian Reanalysis of Overall and Sex-Disaggregated Results in the NeOProM Studies: Implications for Neonatal Health Outcomes in the Context of Antioxidants and Oxidative Stress (antioxidants-2937255)
This article presents a Bayesian reanalysis of the Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol (NeOProM), focusing on the evaluation of health outcomes related to antioxidants and oxidative stress in newborns. Employing Bayes factors (BFs), this reanalysis assesses the likelihood of data under various models considering the presence versus absence of effects, heterogeneity, and moderation by sex. The objective of this study is to investigate whether the reanalysis confirms or alters the findings of previous studies within the NeOProM project. The results of this reanalysis demonstrate moderate evidence in support of no differences (H0) between SpO2 targets in relation to death or major disability (BF10=0.30). However, there is moderate evidence (BF10=3.60) indicating a lower mortality rate in the higher SpO2 group.
Comments:
In the title, it is recommended to either replace or explain the acronym "NeOProM" as the "Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol".
In the abstract, given that this is a reanalysis, it would be valuable, similar to the main text, to report whether the results of this reanalysis confirm or diverge from previous findings within this project. Additionally, the study's objective should be clearly stated in the abstract.
While the introduction provides rationale for the reanalysis, it lacks information on the previous findings of the five articles utilized, which are essential for understanding the obtained results.
The results section is detailed; however, as this is a reanalysis, it should compare previous findings with those obtained using the new methodology to identify differences and assess the contribution of this new analytical approach.
The conclusions should directly address the study objectives. It would be beneficial to understand the novel contributions of this reanalysis in comparison to the previous results of the utilized articles.
In the context of this reanalysis, it would be enriching not only to present the results derived from the application of Bayesian analysis methodology and its conclusions but also to contrast them with the previous findings of the five articles upon which this study is based. Comparing the results obtained with this new analytical perspective to those previously documented could shed light on potential discrepancies, methodological improvements, or novel contributions to the field of study.
It would be valuable for the discussion to assess the contribution brought forth by this new perspective of data reanalysis.
Title: A Bayesian Reanalysis of Overall and Sex-Disaggregated Results in the NeOProM Studies: Implications for Neonatal Health Outcomes in the Context of Antioxidants and Oxidative Stress (antioxidants-2937255)
This article presents a Bayesian reanalysis of the Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol (NeOProM), focusing on the evaluation of health outcomes related to antioxidants and oxidative stress in newborns. Employing Bayes factors (BFs), this reanalysis assesses the likelihood of data under various models considering the presence versus absence of effects, heterogeneity, and moderation by sex. The objective of this study is to investigate whether the reanalysis confirms or alters the findings of previous studies within the NeOProM project. The results of this reanalysis demonstrate moderate evidence in support of no differences (H0) between SpO2 targets in relation to death or major disability (BF10=0.30). However, there is moderate evidence (BF10=3.60) indicating a lower mortality rate in the higher SpO2 group.
Comments:
In the title, it is recommended to either replace or explain the acronym "NeOProM" as the "Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol".
In the abstract, given that this is a reanalysis, it would be valuable, similar to the main text, to report whether the results of this reanalysis confirm or diverge from previous findings within this project. Additionally, the study's objective should be clearly stated in the abstract.
While the introduction provides rationale for the reanalysis, it lacks information on the previous findings of the five articles utilized, which are essential for understanding the obtained results.
The results section is detailed; however, as this is a reanalysis, it should compare previous findings with those obtained using the new methodology to identify differences and assess the contribution of this new analytical approach.
The conclusions should directly address the study objectives. It would be beneficial to understand the novel contributions of this reanalysis in comparison to the previous results of the utilized articles.
In the context of this reanalysis, it would be enriching not only to present the results derived from the application of Bayesian analysis methodology and its conclusions but also to contrast them with the previous findings of the five articles upon which this study is based. Comparing the results obtained with this new analytical perspective to those previously documented could shed light on potential discrepancies, methodological improvements, or novel contributions to the field of study.
It would be valuable for the discussion to assess the contribution brought forth by this new perspective of data reanalysis.
Author Response
Answer: Thank you very much for the positive evaluation of our manuscript and the constructive comments and criticisms.
Following your suggestion the meaning of the acronym has been included in the title.
In the abstract, given that this is a reanalysis, it would be valuable, similar to the main text, to report whether the results of this reanalysis confirm or diverge from previous findings within this project. Additionally, the study's objective should be clearly stated in the abstract.
Answer: We included the following sentence in the abstract: “Aiming to re-evaluate the strength of this evidence, we conducted a Bayesian reanalysis of the NeOProM data”. In addition, we state in the abstract that our results confirm the previous results of the NeOproM studies. Due to the limited number of words in the abstract it is difficult to elaborate on this point. In the manuscript, we did elaborate on the contribution of our Bayesian reanalysis to the interpretation of the strength of evidence from the NeOProM collaborative data.
While the introduction provides rationale for the reanalysis, it lacks information on the previous findings of the five articles utilized, which are essential for understanding the obtained results. The results section is detailed; however, as this is a reanalysis, it should compare previous findings with those obtained using the new methodology to identify differences and assess the contribution of this new analytical approach. The conclusions should directly address the study objectives. It would be beneficial to understand the novel contributions of this reanalysis in comparison to the previous results of the utilized articles. In the context of this reanalysis, it would be enriching not only to present the results derived from the application of Bayesian analysis methodology and its conclusions but also to contrast them with the previous findings of the five articles upon which this study is based. Comparing the results obtained with this new analytical perspective to those previously documented could shed light on potential discrepancies, methodological improvements, or novel contributions to the field of study. It would be valuable for the discussion to assess the contribution brought forth by this new perspective of data reanalysis.
Answer: In the new version of the manuscript, we have tried to address the shortcomings that you point out. We have included specific information on the original results of the NeOProM collaboration and compared them with the results of our Bayesian reanalysis. To facilitate the comparison between the original results and our Bayesian reanalysis, we have included three new tables in the supplementary material (Tables S4-S6). These tables compare the p-values of the original frequentist analysis with the Bayes factors of the Bayesian reanalysis.
We have also tried to emphasize the contribution and novelty of our Bayesian reanalysis. The following paragraphs have been added or substantially rewritten:
Introduction:
“This prospective meta-analysis used harmonized individual participant data from five randomized controlled trials (RCTs) involving approximately 5,000 infants [12-17]. The RCTs were the SUPPORT (Surfactant, Positive Pressure and Oxygenation Randomized Trial), the three (Australia, New Zealand, and United Kingdom) BOOST II (Benefits of Oxygen Saturation Targeting II), and the COT (Canadian Oxygen Trial) [12-17]. The five trials included similar populations of extremely preterm infants, compared the same target SpO2 ranges, used similarly modified investigational oximeters to mask for allocation of the groups, and investigated the same short- and long-term outcomes. The NeOProM data showed that targeting a lower SpO2 range (85%-89%) versus a higher SpO2 range (91%-95%) increased mortality with a risk ratio (RR) of 1.17 and a 95% confidence interval (CI) of 1.04 to 1.31 (P = 0.01). The lower saturation range was also associated with an increased risk of developing severe NEC (RR 1.33, 95% CI 1.10 to 1.61, P=0.003), but decreased the risk of developing severe ROP (RR 0.81, 95% CI 0.74 to 0.90, P<0.001) [11].”
Discussion:
“The main contribution of this Bayesian reanalysis is that it allows an assessment of the strength of evidence for the different results of the NeOProM collaboration. It also provides a way to differentiate between evidence of absence and absence of evidence.”
“The results of the NeOProM trials were not significant for the primary outcome of death or major disability (RR 1.04, 95% confidence interval 0.98 to 1.09, P = 0.21) [11]. In the case of non-significant or null results, clinicians need to be able to gauge the evidence of the absence of an effect [44]. However, the frequentist approach does not allow us to distinguish whether the null results indicate evidence for the absence of differences between the two saturation ranges or whether they are inconclusive (i.e., absence of evidence). Here we have shown how this goal of distinguishing between the two situations can be achieved by using BFs. The BF10 for the outcome of death or major disability in the NeoProM trials was 0.30. Consequently, the BF01 was 3.33 (1/0.3=3.33). This means that the data are 3.33 times more likely under H0 than under H1, which is considered moderate evidence in favor of H0 (no differences between the two saturation ranges).”
“Despite the limitations mentioned above, the RCTs included in the NeOProM collaboration showed differences between the two saturation ranges in several key outcomes, including mortality. The SUPPORT trial, the first of the NeOProM collaboration to report in-hospital outcomes, reported no difference in the composite primary outcome of death or ROP, but showed evidence that targeting SpO2 in the lower range (85% to 89%) was associated with an unanticipated higher mortality rate (RR 1.27; 95% CI, 1.01 to 1.60; P=0.04) [13]. A subsequent safety meta-analysis of the SUPPORT trial along with the three BOOST II trials reported significantly lower mortality in the higher-target group (91% to 95%). As a result, enrollment in two of the BOOST II trials was stopped early because further enrollment could cause harm to participants [58]. Finally, the NeOProM meta-analysis confirmed the higher mortality associated with the lower SpO2 range (RR 1.17, 95% CI 1.04 to 1.31, P = 0.01) [11].”
“The NeOProM project is a major achievement and a milestone in international neonatal research collaboration and has had a profound impact on clinical practice. The potential association of the lower SpO2 range (85-89%) with increased mortality and development of NEC led many NICUs worldwide to implement saturation ranges close to the high ranges studied in the trials (91-95%), as recommended by scientific panels and organizations [68-70]. However, it should be noted that preterm infants have probably individually different susceptibility to the damage caused by either hypoxia or hyperoxia [52-57]. Factors as perinatal and neonatal comorbidity, gestational and postnatal age, growth, or therapeutic interventions may have impact on the severity and extent of hypoxic or oxidative stress. Therefore, is unlikely that a single narrow SpO2 range can be found that would be safe for all extremely preterm infants [52-57]. Nevertheless, it does not appear that the efforts of the neonatal research community will be directed towards conducting new RCTs on SpO2 limits. In a search of https://clinicaltrials.gov/, we could not find any ongoing RCT focusing on SpO2 limits in extremely preterm infants outside the birth resuscitation period. “
Author Response File: 
Author Response.pdf
Reviewer 2 Report
This new analysis provides very relevant data. The only point for me is the following:
NEC, BPD and ROP are the oxidative pathologies of the newborn - Can you comment on the oxidant/antioxidant status?
This article is very complete and sexual dimorphism is very important.
Author Response
Answer: Thank you very much for the positive evaluation of our manuscript. Following your suggestion, we have included the following paragraph in the new version of the manuscript
“The Oxygen Paradox states that while oxygen is essential for aerobic life forms, it is also inherently dangerous to those same life forms [1]. Arguably, the moment of life in which this paradox manifests itself in a more pronounced way is the transition from the intrauterine to the extrauterine life. At birth, the newborn is exposed to the oxidative shock of transitioning from the relative hypoxia of fetal life to the atmospheric normoxia of postnatal life [2-4]. While this transition is generally smooth in term infants, because they have adequate antioxidant defenses, this is not the case in premature infants. Furthermore, the physiologically hypoxic intrauterine environment is a major stimulus for the development of organs and systems [5, 6]. Preterm birth disrupts this physiological development, forcing immature organs and systems to assume their physiological functions too early. This alters the type of signals and stimuli that these organs and systems will receive for their subsequent development. Two other aspects need to be taken into account. The first is that an environment of oxidative stress may already have been induced by the pathological condition, or endotype, responsible for preterm birth [7]. The second is that therapeutic interventions such as oxygen supplementation, mechanical ventilation, or parenteral nutrition, together with postnatal exposure to infectious-inflammatory processes, may substantially increase the oxidative stress load [2-4]. Saugstad coined the term “oxygen radical disease of neonatology” in 1981 proposing that oxidative stress has a spectrum of effects in the neonate and might play a role in the pathogenesis of many complications of prematurity, including bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), or necrotizing enterocolitis (NEC) [8].”
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
After carefully reviewing the new version of the manuscript "Aiming to re-evaluate the strength of this evidence, we conducted a Bayesian reanalysis of the NeOProM data", I would like to express my gratitude to the authors for their effort in incorporating the requested clarifications. However, I believe that, since this is a reanalysis, it is essential to clearly identify what this new perspective contributes compared to previously published articles. To initiate the discussion, the phrase "The main contribution of this Bayesian reanalysis is that it allows an assessment of the strength of evidence for the different results of the NeOProM collaboration. It also provides a way to differentiate between evidence of absence and absence of evidence" should be more precise and specific.
I appreciate the effort made by the authors in presenting supplementary information.
After carefully reviewing the new version of the manuscript "Aiming to re-evaluate the strength of this evidence, we conducted a Bayesian reanalysis of the NeOProM data", I would like to express my gratitude to the authors for their effort in incorporating the requested clarifications. However, I believe that, since this is a reanalysis, it is essential to clearly identify what this new perspective contributes compared to previously published articles. To initiate the discussion, the phrase "The main contribution of this Bayesian reanalysis is that it allows an assessment of the strength of evidence for the different results of the NeOProM collaboration. It also provides a way to differentiate between evidence of absence and absence of evidence" should be more precise and specific.
I appreciate the effort made by the authors in presenting supplementary information.
Author Response
Thank you again for the critical and careful review of the manuscript and the positive appreciation of the changes we have made.
Following your suggestion, we have rewritten the first sentences of the discussion as follows:
“The NeOProM collaboration have provided the highest quality of evidence on what SpO2 ranges are most appropriate for extremely preterm infants during the first weeks of life. The main contribution of this Bayesian reanalysis is that it allows an assessment of the strength of this evidence in a way that goes beyond the dichotomous categorization (significant vs. non-significant) of classical frequentist statistics.”
We believe that this highlights both the relevance of the original study (NeOProM) and the contribution of our reanalysis. The idea of the relevance of reanalysis and categorization of evidence using a Bayesian approach is developed in depth throughout the discussion.
