The British Medical Journal has retracted an article examining when unexpected weight loss could be a warning sign of cancer after the authors found an error in their work.
Retraction Watch reports that the journal has published an updated version of the analysis with different conclusions, which the authors think could influence patient care.
The retracted paper, “Prioritising primary care patients with unexpected weight loss for cancer investigation: diagnostic accuracy study”, appeared on 13 August 2020.
The researchers, led by Brian D Nicholson, a general practitioner and associate professor in the Nuffield Department of Primary Care Health Sciences at the University of Oxford, England, used electronic health records data to look for people diagnosed with cancer within six months of a recording of unexpected weight loss.
The authors were attempting to replicate their results in another dataset when they found “some differences in the study findings and study population that we could not easily explain”, Nicholson told Retraction Watch.
“For many months we tried hard to understand what could have caused these differences. As part of our investigation, we reviewed the processes that had been used to select the study population included in the analysis and identified that … an unanticipated selection bias might have been introduced while the dataset had been prepared for the analysis”.
Nicholson and his colleagues contacted The BMJ when they felt they could “articulate what we thought had happened”, he said.
“We found the journal very responsive to our approach for advice about what we should do next,” he added.
On 25 March, the journal published an expression of concern: “The authors of the paper recently identified an error in their approach to the research. Some patients were excluded from the study because their healthcare records contained a code that was not associated with weight loss. Some time later, however, some of these patients are likely to have had a code included in their healthcare record that was associated with unintended weight loss and cancer. This created an unintended selection bias in the work; some patients were excluded from the study who should have been included in the study.
“Rectifying this error would result in substantially more patients being included in the study. Re-analysis changes the study’s key results and messages. It corrects an underestimate of the likelihood of cancer for some men, and a larger group of women.
“BMJ is working with the authors to review a new version of the paper and to determine what post-publication action is suitable in this case. An update will be provided when our evaluation has concluded.”
The journal ultimately decided to publish an updated version of the article, and the authors were “relieved”, Nicholson said.
The retraction notice, published on 16 October, stated the authors and journal agreed to retract the flawed paper, and linked to the updated version.
The notice was largely the same as the expression of concern, but elaborated on the effect of excluding the patients who should have been included.
The exclusions “caused the study to underestimate the prevalence of cancer in the general primary care population”, the notice stated.
The original study included nearly 64 000 patients with unexpected weight loss recorded in their medical records between 2000-2012, of whom 1.4% ended up receiving a cancer diagnosis within six months.
In the update, the authors analysed records from about 326 000 patients with unexpected weight loss between 2000-2019. This time, 4.8% had received a cancer diagnosis half a year later.
The results also changed. The first analysis found unexpected weight loss indicated a high enough risk of cancer to warrant follow-up investigation only for men at least 50 years old who had smoked and people with additional symptoms.
The re-analysis which found unexpected weight loss in all men at least 50 years old and women at least 60 years old, as well as younger patients with additional symptoms, indicated “the risk of cancer warrants referral for invasive investigation”.
The BMJ “has contacted those who have cited the work to alert them to the new results in the updated version of the paper”, according to a spokesperson for the journal.
The authors and The BMJ have also contacted the UK’s National Institute for Health and Care Excellence (NICE) “because the paper could inform recommendations about which individuals should be referred to specialist services with unexplained weight loss in primary care”.
The retracted article has been cited 15 times, according to Clarivate’s Web of Science, with four citations since the March expression of concern.
The revised results have not yet been reported as widely as the first article, according to Altmetric, which tracks the online attention articles receive.
“Our updated results report the risk of cancer in patients attending their GP with unexpected weight loss,” Nicholson said. “We hope these results will be taken into account when our national guidelines, and other international clinical guidelines, are updated about who should be urgently referred for cancer investigation.”
Updated study details
Prioritising primary care patients with unexpected weight loss for cancer investigation: diagnostic accuracy study (update)
BD Nicholson, P Virdee, P Aveyard, SJ Price, FDR Hobbs, C Koshiaris, W Hamilton.
Published in The BMJ on 21 November 2024
Objective
To quantify the predictive value of unexpected weight loss for cancer according to patient’s age, sex, smoking status, and concurrent clinical features (symptoms, signs, and abnormal blood test results).
Design
Diagnostic accuracy study (update).
Setting
Data from Clinical Practice Research Datalink electronic health records linked to the National Cancer Registration and Analysis Service in primary care, England.
Participants
326 240 adults (≥18 years) with a code for unexpected weight loss from 1 January 2000 to 31 December 2019.
Main outcome measures
Cancer diagnosis in the six months after the earliest weight loss code (index date). Codes for additional clinical features were identified in the three months before to one month after the index date. Diagnostic accuracy measures included positive and negative likelihood ratios, positive predictive values, and diagnostic odds ratios.
Results
Of 326 240 adults with unexpected weight loss, 184 270 (56.5%) were women, 176 508 (54.1%) were aged ≥60 years, and 176 053 (54.0%) were ever smokers. 15 624 (4.8%) had a diagnosis of cancer within six months of the index date, of whom 15 051 (96.3%) were aged ≥50 years. The positive predictive value for cancer was above the 3% threshold recommended by the National Institute for Health and Care Excellence for urgent investigation in men aged ≥50 years and women aged ≥60 years. 17 additional clinical features were associated with cancer in younger men with unexpected weight loss, and eight in women. Positive likelihood ratios in men ranged from 1.43 (95% confidence interval 1.30 to 1.58) for fatigue to 21.00 (8.59 to 51.37) for rectal mass, and in women from 1.28 (1.16 to 1.41) for back pain to 19.46 (12.69 to 29.85) for pelvic mass. Abnormal blood test results associated with cancer included low albumin (positive likelihood ratio 3.24, 3.13 to 3.35) and raised platelets (3.48, 3.35 to 3.62), total white cell count (3.01, 2.89 to 3.14), and C reactive protein (3.13, 3.05 to 3.20). However, no normal blood test result in isolation ruled out cancer. Clinical features co-occurring with unexpected weight loss were associated with multiple cancer sites.
Conclusion
The risk of cancer in younger adults with unexpected weight loss presenting to primary care is <3% and does not merit investigation under current UK guidelines. However, in men aged ≥50 years, women aged ≥60 years, and younger patients with concurrent clinical features, the risk of cancer warrants referral for invasive investigation. Clinical features typically associated with specific cancer sites are markers of several cancer types when they occur with unexpected weight loss.
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