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16S rRNA gene sequencing and healthy reference ranges for 28 clinically relevant microbial taxa from the human gut microbiome

Authors: Daniel E. Almonacid,Laurens Kraal,Francisco J. Ossandon,Yelena V. Budovskaya,Juan Pablo Cardenas,Elisabeth M. Bik,Audrey D. Goddard,Jessica Richman,Zachary S. Apte
Publisher: Public Library of Science (PLoS)
Publish date: 2017-5-3
ISSN: 1932-6203 DOI: 10.1371/journal.pone.0176555
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There are serious issues with the paper titled, “16S rRNA gene sequencing and healthy reference ranges for 28 clinically relevant microbial taxa from the human gut microbiome” (DOI: 10.1371/journal.pone.0176555), authored by Almonacid et al., published in PLOS ONE in 2017. While the Expression of Concern issued on October 20, 2022, acknowledges some of these problems, it’s necessary for the authors to fully address them due to the broader implications for scientific integrity.

I previously attempted to raise these significant concerns on PubPeer on November 19, 2024; however, my comments were completely censored by the moderator and never published.

1- Questionable Data Integrity: The Expression of Concern has already noted that one sample (sample 757) may have originated from a non-human source, raising questions about data verification practices. The presence of potentially non-human data in a study purporting to define “healthy human” microbiome reference ranges compromises the validity of its conclusions and indicates potential systematic oversights that could affect other data points.

2- Reliance on Self-Reported Participant Health: The reliance on self-reported data without independent medical verification is a significant weakness, especially in a study establishing baseline microbiome health metrics. This methodology introduces a substantial risk of undetected medical conditions among participants, potentially skewing results and reducing the credibility of the reported healthy reference ranges.

Looking forward to a constructive discussion.

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2 weeks ago

I thank the SG Participant for their comments. Both comment have been acknowledged in the Expression of Concern, so I am not sure which new concerns the Participant is trying to raise.

Ad 1. One of the samples indeed may have been of non-human origin, as already mentioned in the EoC. The emphasis is on may, as one customer sent in multiple samples, and they were not clearly labeled. While we might regret that one out of nearly 900 samples might not have been carefully selected, there might be reasons to assume the correct, human, sample was included in the study. Looking at the microbiome composition of this particular sample, it is not an outlier at all, falling within the ranges of the human samples. So it did not skew the results in my opinion. 

Ad 2. The study is clearly marked as relying on self-reported health data. In that respect, it is not unique. Many studies use questionnaires in which participants self-report their feelings, income, weight, health, and other data. Even though researchers know those answers might not be completely reliable, they would still publish papers based on those questionnaires. With large datasets like the one reported in this paper (nearly 900 samples), we assume data might have been reported correctly – that is an assumption that is not unique for this study. 

Both of these points have been raised and answered in the EoC – which is why this discussion feels a bit old. Were there any new issues the SG Participant wanted to raise or did I miss them?

 

1 week, 6 days ago

Thank you for your response. However, with all due respect, your reply does not address the core concerns raised, and unfortunately misrepresents the gravity of the unresolved issues.

The Expression of Concern merely acknowledges that sample 757 may not have been human, but it does not address the real problem. No full audit of the entire dataset was conducted after this discovery. No validation has been provided to demonstrate that the rest of the dataset is free from similar contamination. Nor was there a transparent removal or reanalysis excluding this questionable sample.

Relying on the assumption that a sample “falls within human ranges” is methodologically unsound and scientifically indefensible. Similarity to human microbiota does not guarantee human origin; particularly given well-documented overlaps in microbial profiles between species. The integrity of the full dataset remains compromised by this unresolved uncertainty. This alone should have triggered a withdrawal or retraction, not a dismissive footnote.

Regarding the reliance on self-reported health data, it is critical to distinguish between subjective survey studies and studies that claim to establish clinical diagnostic reference ranges. This study aimed to define “healthy” microbiome baselines for potential clinical use, yet did so with no independent medical verification of participant health. That is not a minor limitation; it is a fatal flaw that invalidates the clinical claims made, both within the paper and through related commercial activities.

The Expression of Concern vaguely acknowledges this but fails to address the full significance: the study’s core premise is invalid.

What has been presented here is not simply a repetition of old concerns. It is a comprehensive scientific and ethical indictment: dataset contamination risks without reassessment, invalid clinical assumptions based on unreliable self-reports, loss of reproducibility, and misleading clinical claims unsupported by robust evidence. These are foundational problems that strike at the validity of the entire paper.

It would have been an honorable and responsible act for the authors to voluntarily request retraction upon realizing that critical elements of their dataset and methods could not withstand scrutiny. Instead, the approach taken appears focused on minimizing, excusing, and deflecting. That is not scientific integrity; it is damage control.

In summary, the Expression of Concern does not resolve these issues. The article remains fundamentally flawed. The scientific record remains tainted. It is profoundly disappointing that, rather than taking responsibility and retracting the article, the authors continue to dismiss legitimate and serious concerns.

For the credibility of the scientific community, and out of respect for patients and clinicians who rely on accurate standards, the appropriate corrective action remains retraction.

1 week, 2 days ago

While waiting for the authors to address the previous concerns, there is another major issue with this article as follows:

 

“3- Age Variability Concerns
The inclusion of participants spanning an age range from 19 days to 103 years further complicates the study’s claims. Microbiome compositions can vary significantly with age, and the lack of stratified analysis undermines the validity of drawing generalized conclusions about healthy ranges. This gap points to insufficient methodological rigor in addressing age-related variances, essential for a study claiming to inform clinical practice.”

 

Could the authors please address this issue as well?

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