The primary purpose of this response letter is to update the protocol to revise the sample size of the Compass Trial.
Summary
Compass is a randomised controlled trial, operating alongside the Australian National Cervical Screening Program (NCSP). Under the auspices of the Independent Data Safety Monitoring Committee (IDSMC) and Scientific Advisory Committee (SAC) we have performed a re-analysis of our original estimate of the total trial sample size. This was prompted by two factors: (1) impact of the NCSP transition to primary HPV screening and (2) emergence of new evidence relevant to the sample size calculation. With consideration to the resource implications of the renewed program on trial recruitment and acknowledging that the original sample size of 121,000 women for the main trial was calculated in 2014 (prior to the emergence of new relevant evidence) the trial sample size was re-estimated.
The sample size recalculation has resulted in a reduced recruitment target for the cohort of women in Compass Trial who were age-eligible for publicly funded HPV vaccination in Australia (the younger cohort) from 84,700 to 40,000 women; consequently the total recruitment target has been revised from 121,000 to 76,300. The updated sample size estimate has been approved by the Human Research Ethics Committee and is reflected in the trial registration (ClinicalTrials.gov Identifier: NCT02328872).
(1) Impact of the NCSP transition to primary HPV scree...
The primary purpose of this response letter is to update the protocol to revise the sample size of the Compass Trial.
Summary
Compass is a randomised controlled trial, operating alongside the Australian National Cervical Screening Program (NCSP). Under the auspices of the Independent Data Safety Monitoring Committee (IDSMC) and Scientific Advisory Committee (SAC) we have performed a re-analysis of our original estimate of the total trial sample size. This was prompted by two factors: (1) impact of the NCSP transition to primary HPV screening and (2) emergence of new evidence relevant to the sample size calculation. With consideration to the resource implications of the renewed program on trial recruitment and acknowledging that the original sample size of 121,000 women for the main trial was calculated in 2014 (prior to the emergence of new relevant evidence) the trial sample size was re-estimated.
The sample size recalculation has resulted in a reduced recruitment target for the cohort of women in Compass Trial who were age-eligible for publicly funded HPV vaccination in Australia (the younger cohort) from 84,700 to 40,000 women; consequently the total recruitment target has been revised from 121,000 to 76,300. The updated sample size estimate has been approved by the Human Research Ethics Committee and is reflected in the trial registration (ClinicalTrials.gov Identifier: NCT02328872).
(1) Impact of the NCSP transition to primary HPV screening
In December 2017, the NCSP underwent a process known as ‘Renewal’ which saw the program transition from 2-yearly conventional cytology in women aged 18/20–69 years (similar to the control arm in Compass) to 5-year primary HPV screening with partial genotyping for HPV16/18 in women aged 25–74 years (similar to the intervention arm of Compass). The Compass pilot study began recruitment in 2014, followed by the initiation of recruitment of the main trial in 2015, both of which have provided a sentinel experience for Renewal. The transitional implications of Renewal on the Australian healthcare system were extensive,1 and from early 2017 a decrease in the overall Compass monthly recruitment rate was noted which were likely due to the workload and other resourcing implications of the program transition.
However, analysis of recruitment data has demonstrated that the decrease in overall recruitment appears to be related to the number of actively recruiting practitioners and not the recruitment rate experienced among actively recruiting practitioners. The recruitment rate remains very high for practitioners and practices who continue to recruit, with an average recruitment rate of >80% for active practitioners (defined as those who have sent at least 1 cervical sample for the Compass trial to VCS within the calendar month), between December 2017 and November 2019. Therefore, women approached to participate in the trial have continued to choose to participate at a very high rate, indicating broad acceptability of the trial from the perspective of potential participants. Nevertheless, the trial investigators have judged that continuing to recruit at the current rate has become impractical.
(2) Emergence of new evidence relevant to the sample size calculation.
The sample size re-estimate has been based on extensive modelling of the effects of accounting for emergent data on HPV vaccine effect in the Australian population and emergent outcomes from the Canadian HPV FOCAL Trial.2 A total average CIN3+ rate at exit in the Compass LBC arm of 0.94% will now be assumed, based on updated national Australian data on vaccine coverage rate in the age-cohorts captured in trial recruitment (of 59.1%) and a consequent assumed overall population-level vaccine effectiveness rate against CIN3+ in the trial cohort of 20%.3, 4
Changes to protocol
The change in target sample size has impacted the following sections of this protocol paper:
Abstract- Method and Analysis
Original Article: A total of 36,300 women in birth cohorts not offered vaccination and 84,700 women in cohorts offered vaccination will be recruited, bringing the final sample size to 121,000.
Amend To: A total of 36,300 women in birth cohorts not offered vaccination and 40,000 women in cohorts offered vaccination will be recruited, bringing the final sample size to 76,300.
Primary outcomes, statistical design and sample size calculations
Original Article: Assuming a total average cervical intraepithelial neoplasia grade 3 (CIN3) or more severe diagnoses (CIN3+) rate in the liquid-based cytology (LBC) arm (across unvaccinated and vaccinated women) of 0.60%, and an absolute non-inferiority margin of 0.22%, the trial will have >90% power with 97.5% confidence to detect non-inferiority for the human papillomavirus (HPV) arm, allowing for a 10% non-compliance rate. This sample is adequately powered to detect this margin should the LBC rates be higher than the assumed 0.60%. The non-inferiority comparison will be one sided and all other comparisons will be two sided. All comparisons will use a 0.05 level of significance.
Amend To: A total average CIN3+ rate at exit in the Compass LBC arm of 0.94% will be assumed, based on updated national Australian data on vaccine coverage rate in the age-cohorts captured in trial recruitment (of 59.1%) and a consequent assumed overall population-level vaccine effectiveness rate against CIN3+ in the trial cohort of 20%. Assuming an absolute non-inferiority margin of 0.22% (as per trial registration), with a total recruitment of 40,000 in the younger cohort, the trial will have 78% power with 97.5% confidence to detect non-inferiority for the HPV arm, allowing for a 15% non-compliance rate.
Original Article: A total of 36,300 women in the birth cohorts not offered vaccination and 84,700 women in the cohorts offered vaccination will be recruited, bringing the final sample size to 121,000. Of these, 7,700 women will be recruited for a safety monitoring sample (10% of HPV screen-negative participants presenting for routine screening). Those presenting for routine follow-up (approximately 5%) will be assigned to the management branch of the arm to which they will be randomised. These women, however, will not be included in the analysis for the primary outcome.
Amend To: A total of 36,300 women in the birth cohorts not offered vaccination and 40,000 women in the cohorts offered vaccination will be recruited, bringing the final sample size to 76,300. Of these, 4,414 women will be recruited for a safety monitoring sample (10% of HPV screen-negative participants presenting for routine screening). These women, however, will not be included in the analysis for the primary outcome. Those presenting for routine follow-up (approximately 5%) will be assigned to the management branch of the arm to which they will be randomised.
Original Article: For this critical secondary outcome, the sample size for women not offered vaccination was based on estimated CIN3+ rates at 5 years in women who test cytology negative and HPV negative at baseline (round 1) of 0.48% and 0.26%, respectively, estimated rates of negative cytology tests at baseline of 90.8% (VCCR 2012, unpublished data) and a loss to follow-up rate of 5% in each arm. For women who were offered vaccination, the sample size was based on an estimated three-dose vaccination coverage of 75% and an estimated overall population-level vaccine effectiveness of 70% (from a specific modelled analysis to support these estimates), estimated CIN3+ rates at 5 years in women who test cytology negative and HPV negative at baseline (round 1) of 0.23% and 0.12%, estimated rates of negative cytology tests at baseline of 82% (VCCR 2012, unpublished data) and a loss to follow-up rate of 5% in each arm.
Amend To: For this critical secondary outcome, the sample size for women not offered vaccination was based on estimated CIN3+ rates at 5 years in women who test cytology negative and HPV negative at baseline (round 1) of 0.48% and 0.26%, respectively, estimated rates of negative cytology tests at baseline of 90.8% (VCCR 2012, unpublished data) and a loss to follow-up rate of 5% in each arm. For women who were offered vaccination, the sample size was based on an estimated three-dose vaccination coverage of 59.1% and an estimated overall population-level vaccine effectiveness of 20% against CIN3+, estimated CIN3+ rates at 5 years in women who test cytology negative and HPV negative at baseline (round 1) of 0.48% and 0.25%, respectively, estimated rates of negative cytology tests and negative HPV tests at baseline of 88% and 86%, respectively, and a loss to follow-up rate of 15% in each arm.
Performance of dual-stained cytology versus LBC as a triage test
Original Article: Based on pilot study results,27 we expect that after 1-year follow-up for triage-negative women and subsequent referrals are taken into account, the performance of LBC (at a pHSIL/ASC-H threshold) and DS to detect CIN2+ in women with other high-risk (OHR) HPV will be broadly comparable. However, DS is expected to improve immediate detection of CIN2+ and thus minimise loss to follow-up at 12 months, thus increasing CIN2+ detection overall within a ‘real world’ screening programme.
We will use closed loop testing, and if non-inferiority is satisfied we will test for superiority for immediate detection of CIN2+ in the DS versus the LBC group. Analysis will be stratified by age eligibility for vaccination. About 24 200 participants who were not eligible for HPV vaccination will be randomised to the HPV arm. Of these, approximately 22 290 (95%) will be in routine screening at recruitment and about 784 (3.4%) of these will test OHR HPV positive. Assuming an immediately detected CIN2+ rate of 8.2% in the LBC triage arm (based on pilot study results), and an absolute non-inferiority margin of −5.5%, the trial will have 80% power with 97.5% confidence to detect non-inferiority for the DS triage group. About 56 468 participants who were eligible for HPV vaccination will be randomised to the HPV arm. Of these, approximately 53 645 (95%) will be in routine screening at recruitment and about 7548 (14.1%) of these will test OHR HPV positive. Assuming an immediately detected CIN2+ rate of 5.0% in the LBC triage sub-arm (based on pilot study results), and an absolute non-inferiority margin of −1.5%, the trial will have more than 80% power with 97.5% confidence to detect non-inferiority for the DS triage sub-arm.
Amend To: Based on pilot study results,5 we expect that after 1-year follow-up for triage-negative women and subsequent referrals are taken into account, the performance of LBC (at a pHSIL/ASC-H threshold) and DS to detect CIN2+ in women with other high-risk (OHR) HPV will be broadly comparable. However, DS may improve immediate detection of CIN2+ and thus minimise loss to follow-up at 12 months of those diagnosed with CIN2+, potentially increasing CIN2+ detection overall within a ‘real world’ screening programme.
This immediate detection of CIN2+ in the DS group versus the LBS group will first be tested for non-inferiority, and if non-inferiority is declared the outcome will be tests for superiority. We will use closed loop testing, and if non-inferiority is satisfied we will test for superiority for immediate detection of CIN2+ in the DS versus the LBC group. Analysis will be stratified by age eligibility for vaccination. About 24 200 participants not eligible for HPV vaccination will be randomised to the HPV arm. Of these, approximately 22 290 (95%) will be in routine screening at recruitment and about 784 (3.4%) of these will test OHR HPV positive. Assuming an immediately detected CIN2+ rate of 8.2% in the LBC triage arm (based on pilot study results), and an absolute non-inferiority margin of −5.5%, the trial will have 80% power with 97.5% confidence to detect non-inferiority for the DS triage sub-arm. About 26 667 participants eligible for HPV vaccination will be randomised to the HPV arm. Of these, approximately 22 400 (84%) will be in routine screening at recruitment and about 3024 (13.5%) of these will test OHR HPV positive. Assuming an immediately detected CIN2+ rate of 5.0% in the LBC triage sub-arm (based on pilot study results), and an absolute non-inferiority margin of −2.3%, the trial will have more than 80% power with 97.5% confidence to detect non-inferiority for the DS triage sub-arm.
Anticipated recruitment and analysis timing
Original Article: Recruitment for the pilot study began in 2013 and the recruitment target was met in late 2014. Recruitment for the main trial began in January 2015 and the target of 121 000 participants is anticipated to be attained in 2018. Final timing of analysis will be contingent on timing of recruitment in each arm. The timing for each planned analysis accounts for an additional period of 9 months added to allow for 3 months’ follow-up delay and 6 months to obtain histology outcomes.
For participants who were not age eligible for HPV vaccination, baseline analysis (including 12-month follow-up of those managed via 12-month surveillance) will be conducted in approximately January 2018. Analysis for the 2.5-year screening round (Arm A) and 2.5-year safety monitoring analysis (Arm B) is planned for July 2019, and analysis for the final 5-year outcomes is anticipated in early 2022. For participants who were age eligible for HPV vaccination, baseline analysis (including 12-month follow-up) for a subset for which sufficient follow-up is available is anticipated in approximately January 2018. Final baseline screening round analysis is anticipated in 2019–2020. The 2.5-year screening round (Arm A) and the 2.5-year safety monitoring analysis (Arm B) are anticipated in 2021–2022, and the final 5-year outcome analysis is expected in 2023–2024. Thus, the estimated trial completion date is 2024 although as noted long term passive follow-up through registries will also be conducted, pending ethical approval for such follow-up.
Amend To: Recruitment for the pilot study began in 2013 and the recruitment target was met in late 2014. Recruitment for the main trial began in January 2015 and the target of 76,000 participants is anticipated to be attained in late 2019. Final timing of analysis will be contingent on timing of recruitment in each arm. The timing for each planned analysis accounts for an additional period of 9 months - to allow for 3 months’ follow-up delay and 6 months to obtain histology outcomes.
Baseline analysis (cross sectional outcomes for CIN2+ and CIN3+ detection in each arm at baseline, with no surveillance) for both cohorts will be conducted in 2020. 12-month follow-up analysis for both cohorts will be conducted in 2021. Analysis for the 2.5-year screening round (Arm A) and 2.5-year safety monitoring analysis (Arm B) is planned for 2020-2022, and analysis for the final 5-year outcomes is anticipated in 2022-2025. Thus, the estimated trial completion date is 2025 although as noted long term passive follow-up through registries will also be conducted.
Publication revisions related to operational changes
Compass is a real-world randomised controlled trial, operating alongside the Australian National Cervical Screening Program (NCSP). The pragmatic nature of the trial, whilst a strength, does mean the trial is highly influenced by external factors. Over the course of the trial, the following changes have been reflected in the protocol;
• VCS Ltd has been renamed as VCS Foundation.
• Due to decision making at a government level several registers previously held by VCS Foundation were transferred to centralise locations. From the end of 2018 Victorian Cervical Screening Registry (VCCR) and the South Australian Cervix Screening Registry (SACSR) were transferred to the National Cancer Screening Register (NCSR) and the National HPV Vaccination Program Register (NHPVR) was transitioned to the Australian Immunisation Register (AIR). Throughout the entirety of the protocol, all references to VCCR in the protocol should be read as The Compass Register, which is hosted at VCS Foundation.
• The process for exiting participants who have completed all Compass tests in line with the study arm to which they were assigned, who have a normal 5 years screening result, and women who have an abnormal screening result at 5 years and are followed-up until their screening episode has resolved, has been included in the operational protocol. This includes a detailed explanation on the passive follow-up processes, resulting in a change to the “Long-term outcomes” section of the published protocol, as per the below;
Long-term outcomes
Original Article: Pending ethical and data custodian approvals, long-term outcomes will be examined in all participants, including outcomes at 10 and 20 years post-recruitment (although women will return to routine screening practice after 5-year exit testing). Women will be passively followed over time using registry data for long-term outcomes for CIN2+ and CIN3+, and invasive cervical cancer. This will be done for a number of subgroups including women who cease screening at different ages, women who start screening at different ages and women in broad age strata who have different patterns of screening behaviours (eg, regular 5-year screening vs irregular screening or under-screening). We will also assess outcomes in women who access self-collected HPV testing after trial exit as part of the renewed HPV-based cervical screening program in Australia.
Amend To: Following completion of all Compass-related tested, women will be sent an exit letter from the VCS Foundation. The letter will serve to confirm that they have finished trial participation, thank them for their contribution to cervical cancer research and instruct the women on when they should next attend for cervical screening/follow-up. Additionally, the letter will include the information on the transition of their data to the National Cancer Screening Register (NCSR) (unless they opt-off) and inform them that the Compass researchers will access their future cervical screening results through the NCSR for the purpose of long-term analysis (specific analysis will be conducted pending ethical approval) and provide the option to opt-out of further passive follow-up by contacting the free call Compass hotline.
For women who have not opted-out of further passive follow-up, long-term outcomes will be examined in all participants, including outcomes at 10 and 20 years post-recruitment (although women will return to routine screening practice after 5-year exit testing). Women will be passively followed over time using registry data for long-term outcomes for CIN2+, CIN3+, and invasive cervical cancer. This will be done for a number of subgroups including women who cease screening at different ages, women who start screening at different ages and women in broad age strata who have different patterns of screening behaviours (e.g., regular 5-year screening vs irregular screening or under-screening). We will also assess outcomes in women who access self-collected HPV testing after trial exit as part of the renewed HPV-based cervical screening program in Australia
• In the operational protocol we have described the orderly close out of the recruitment phase of the trial. Active recruitment of participants to the trial ceases on the 30th of November 2019, samples which are received at VCS Foundation with a signed consent form on or before the 31st of December 2019 will be randomized into the trial. Any samples received from the 1st January 2020 will be tested and followed-up through the routine NCSP. This impacts the “Recruitment” section of the publication, which should be read as per the below;
Recruitment
Original Article: Potential participants will be identified by medical practitioners or nurses at one of the participating primary healthcare clinics or sexual health clinics. Recruiting practitioners will be shown how to obtain informed consent and the VCS liaison physicians will regularly liaise with practitioners throughout the duration of the trial to support compliance with the study protocol. The practitioner will decide whether the woman is able to make informed consent and if so, invite her to participate in the trial. Eligible women will be given an information sheet to read. If they choose to participate, they will be provided with a consent form to read and sign and will have a routine cervical sample collected into an LBC phial. The LBC sample phial will be labelled and sent to VCS Pathology with the signed patient consent form. Each consent form will be scanned and stored electronically as part of the VCS Pathology laboratory record. Participants will be recruited until the recruitment targets are met for each of the pre-specified age strata.
Amend To: Potential participants will be identified by medical practitioners or nurses at one of the participating primary healthcare clinics or sexual health clinics. Recruiting practitioners will be shown how to obtain informed consent and the VCS liaison physicians will regularly liaise with practitioners throughout the duration of the trial to support compliance with the study protocol. The practitioner will decide whether the woman is able to make informed consent and if so, invite her to participate in the trial. Eligible women will be given an information sheet to read. If they choose to participate, they will be provided with a consent form to read and sign and will have a routine cervical sample collected into an LBC phial. The LBC sample phial will be labelled and sent to VCS Pathology with the signed patient consent form. Each consent form will be scanned and stored electronically as part of the VCS Pathology laboratory record. The recruitment target for the older cohort of women was met in April 2016. The revised recruitment target for the younger cohort of women is anticipated to be met in late 2019. Active recruitment of participants to the trial ceases on the 30th of November 2019, samples that are received at VCS Foundation with a signed consent form on or before the 31st of December 2019 will be randomized into the trial. Any samples received from the 1st January 2020 will be tested and followed-up through the routine NCSP.
• The reference to HPV type 45 being referred to colposcopy has been removed. This is in line with the national guidelines in Australia but not directly applicable to the study as an HPV testing platform which partially genotypes only for HPV16/18 is used in Compass. This has no impact on the trial design or analysis; Figure 1 and Figure 2 from the operational protocol have been revised accordingly.
In relation to this change we attach the following updated document;
Referenced Compass Trial Document:
• Compass Operational Protocol Version 1.8
References
1. Smith M, Hammond I, Saville M. Lessons from the renewal of the National Cervical Screening Program in Australia. Public Health Res Pract. 2019;29(2):e2921914.
2. Ogilvie GS, van Niekerk D, Krajden M, et al. Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months The HPV FOCAL Randomized Clinical Trial. JAMA. 2018;320(1):43–52. doi:10.1001/jama.2018.7464
3. http://www.hpvregister.org.au/research/coverage-data, access date: November 2018
4. Brotherton JML, Lui B, Donovan B, et al. Human papillomavirus (HPV) vaccination coverage in young Australian women is higher than previously estimated: Independent estimates from a nationally representative mobile phone survey.2014; 32(5) 592-597. https://doi.org/10.1016/j.vaccine.2013.11.075.
5. Canfell K , Caruana M , Gebski V , et al . Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: Results of the Compass pilot randomised trial. PLoS Med 2017;14:e1002388.doi:10.1371/journal.pmed.1002388
Thanks to Rydahl et al. for yet an attempt to question a more offensive post-term induction practice to have a main responsibility for the impressing reduction in stillbirths in Denmark (1). The more offensive induction practice was gradually implemented in Denmark through this century but accelerated by the National recommendation in 2010-2011 to induce post-term women so to ensure delivery before 42 gestational weeks (GW).
The following comments assume that the data presented by Rydahl et al. are correct, we are currently looking at the same issue and the same data.
First what we agree on:
• There has from 2000 to 2012 been a substantial decrease in stillbirths in Denmark among women pregnant beyond 41+3 GW. The reduction was from 2.6 to <0.5 stillbirths per 1000 delivered, a reduction of at least 80%. Shouldn’t we start by congratulating each other for this impressing National achievement.
• During the same period has the proportion of induced deliveries increased for women going beyond 41+3 GW from 25% to around 65%.
• Despite this dramatic change in induction practice, both Caesarean section rates, low Apgar scores, and birth augmentation have been almost stable.
• The proportion of instrumental births has decreased during the same period.
It is of course an important issue what caused the dramatic decrease in stillbirths over the last two decades in Denmark. We have previously published evidence arguing that the more offe...
Thanks to Rydahl et al. for yet an attempt to question a more offensive post-term induction practice to have a main responsibility for the impressing reduction in stillbirths in Denmark (1). The more offensive induction practice was gradually implemented in Denmark through this century but accelerated by the National recommendation in 2010-2011 to induce post-term women so to ensure delivery before 42 gestational weeks (GW).
The following comments assume that the data presented by Rydahl et al. are correct, we are currently looking at the same issue and the same data.
First what we agree on:
• There has from 2000 to 2012 been a substantial decrease in stillbirths in Denmark among women pregnant beyond 41+3 GW. The reduction was from 2.6 to <0.5 stillbirths per 1000 delivered, a reduction of at least 80%. Shouldn’t we start by congratulating each other for this impressing National achievement.
• During the same period has the proportion of induced deliveries increased for women going beyond 41+3 GW from 25% to around 65%.
• Despite this dramatic change in induction practice, both Caesarean section rates, low Apgar scores, and birth augmentation have been almost stable.
• The proportion of instrumental births has decreased during the same period.
It is of course an important issue what caused the dramatic decrease in stillbirths over the last two decades in Denmark. We have previously published evidence arguing that the more offensive induction practice has the main responsibility for this decrease (2), and that the increased induction rates did improve neonatal health rather than the opposite and did not increase the Caesarean section rates (3).
Rather than calculating stillbirth rates at different times during the study period 2000-2016, Rydahl et al. argue that slope analyses should be more reliable. The argumentation (if we have understood the authors correctly) goes as follows: During the period 2000-2011 there was a decrease in stillbirth rates in the order of 10% per year. Then during the period 2012-16 we also saw a decrease of the same magnitude (11% per year). Because the decrease was not steeper during the latter period as compared with the former period, the changed recommendation in 2011 and the more offensive induction practice had no influence on the stillbirth rates. This point of view is further supported by making a projection of the fall based on the first period. The constructed prediction model was almost identical with the observed best fitted smooth curve observed, again contradicting any influence from the new induction paradigm.
First, changes in slopes do not trump good old incidence rates and changes in these rates. Next the fall during the first period is coinciding with the doubling of induction from 25% in year 2000 to around 50% in 2011. After 2012 there is no further increase in inductions. Therefore, a further decrease is not to be expected after 2012, rather stable low rates, which is exactly what was reported in the study by Rydahl (Table 2).
So, nothing in the study by Rydahl et al. contradicts in our opinion prevention of stillbirths from earlier and more frequent induction regimens in post-term pregnant women.
Add to this a recent Swedish study randomizing women to induction at 41+0 or 42+0 (4). This study had to be interrupted due to five stillbirths in 1379 women in the 42+0 group of versus zero in the 41+0 group of 1381 women. All other end points were similar for the two groups. As one consequence of this study, women at many maternity wards in Sweden are now routinely induced at 41+0 (at latest).
With this strong scientific evidence of preventing stillbirths by an induction practice starting at 41+0, and in a country with similar obstetrical practice, socioeconomic status, as Denmark, we still think there is overwhelming evidence of a positive influence from an offensive post-term induction practice on post-term stillbirth rates.
Niels Uldbjerg, Professor in Obstetrics, Aarhus University Hospital
Morten Hedegaard, former head of Dept. of Obstetrics, Rigshospitalet
Øjvind Lidegaard, Professor in Obstetrics and Gynaecology, Rigshospitalet
E-mail of corresponding author: Oejvind.Lidegaard@regionh.dk.
References
1. Rydahl E, Declercq E,. Juhl M, Maimburg RD. Routine induction in late-term pregnancies: follow-up a Danish induction of labour paradigm. BMJ Open 2019; 9: e032815.
2. Hedegaard M, Lidegaard Ø, Skovlund CW, Mørch LS, Hedegaard M. Reduction in stillbirths at term after new birth induction paradigm: results of a national intervention. BMJ Open 2014; 4: e005785.
3. Hedegaard M, Lidegaard Ø, Skovlund CW, Mørch LS, Hedegaard M. Perinatal outcomes following an earlier post-term labour induction policy: a historical cohort study. BJOG 2015; DOI: 10.1111/1471-0528.13299
4. Wennerholm U-B, Saltvedt S, Wessberg A, Alkmark M, et al. Induiction of labour at 41 weeks versus expectant management and induction of labour at 42 weeks (SWEdish Post-term Induction Study, SWEPIS): Multicentre, open label, randomized, superiority trial. BMJ 2019; 367: i6131.
We read with interest this paper reporting the results of the ROMPA trial on the efficacy of Coupled Plasma Filtration and Adsorption (CPFA) in reducing mortality in patients with septic shock. The trial was prematurely closed, after we informed the investigators of ROMPA that we had stopped our COMPACT-2 trial, designed on the same topic, for reasons of futility. COMPACT-2 (NCT01639664), whose protocol inspired ROMPA, was prompted by a pre-planned subgroup analysis coming from the overall negative COMPACT trial, suggesting that CPFA might have been effective, had a high volume of plasma been treated.
The first planned interim analysis of COMPACT-2, aimed at assessing the feasibility of the technique, revealed a number of early deaths during CPFA. This induced the External Data and Safety Monitoring Committee (EDSMC) to request an unplanned interim analysis of safety. Such analysis, performed on the 113 recruited patients, showed significantly higher mortality in the CPFA group compared to controls, both at 3 days from randomization and at the 90-day survival analysis. We have now completed the clinical review of each recruited patient, performed through site visits by a team of independent experts, and plan to submit the manuscript to a scientific journal.
In the meantime, we would like to clarify a couple of aspects related to our trial that were misreported in the present article and to comment on some sections of the paper. First, COMPACT-2 was not stopped...
We read with interest this paper reporting the results of the ROMPA trial on the efficacy of Coupled Plasma Filtration and Adsorption (CPFA) in reducing mortality in patients with septic shock. The trial was prematurely closed, after we informed the investigators of ROMPA that we had stopped our COMPACT-2 trial, designed on the same topic, for reasons of futility. COMPACT-2 (NCT01639664), whose protocol inspired ROMPA, was prompted by a pre-planned subgroup analysis coming from the overall negative COMPACT trial, suggesting that CPFA might have been effective, had a high volume of plasma been treated.
The first planned interim analysis of COMPACT-2, aimed at assessing the feasibility of the technique, revealed a number of early deaths during CPFA. This induced the External Data and Safety Monitoring Committee (EDSMC) to request an unplanned interim analysis of safety. Such analysis, performed on the 113 recruited patients, showed significantly higher mortality in the CPFA group compared to controls, both at 3 days from randomization and at the 90-day survival analysis. We have now completed the clinical review of each recruited patient, performed through site visits by a team of independent experts, and plan to submit the manuscript to a scientific journal.
In the meantime, we would like to clarify a couple of aspects related to our trial that were misreported in the present article and to comment on some sections of the paper. First, COMPACT-2 was not stopped simply because of higher 3-day mortality. Rather, the in-depth reasoning behind our decision took account of the significantly higher mortality at the 90-day survival analysis, the close to significantly higher hospital mortality rate (our primary endpoint), and the low conditional power for treatment benefit at the end the study. In this regard, we do not fully follow the authors’ reasoning that a statistically significant difference could be the result of random error. The statistical test is performed for the very purpose of computing the probability that a difference can be attributed to random error. Also, COMPACT-2 did not use a randomization scheme based on prognostic score. We used a blocked randomization schedule (randomly permuting blocks of four and six), with stratification according to site and the presence of septic shock at admission. It is well known that stratified blocked randomization guarantees strict balance between arms. The authors’ statement that stratified randomization “means that the groups will not be similar until the end of recruitment” contrasts with common methodological understanding. In this respect, the high imbalance between the arms of the ROMPA trial (with the control group having 50% more patients than the CPFA arm) cannot be due to the adoption of stratified randomization, irrespective of the random strata. Moreover, we strongly disagree with excluding from the analysis patients assigned to the experimental arm who died before receiving the CPFA treatment. Also in the control group it is to be expected that a similar number of patients would have died too early to receive the experimental treatment, had they been randomized to the CPFA instead of the control arm. Excluding these patients only from the experimental arm introduces a well-recognized bias, which distorts the results. Finally, we decided to inform the ROMPA researcher of our decision to interrupt COMPACT-2 for futility, given the high similarity between the ROMPA trial design and our own. We did not intend in any way to force the ROMPA researcher to adopt the same decision. We find the statement that they were “obliged to communicate” their partial results a little odd, partly considering that their Data and Safety Monitoring Committee was not independent, being formed by the principal investigator, the senior investigator and the biostatistician of the project.
Besides these comments, we find the results of the ROMPA trial interesting, despite being based on a very limited sample size, particularly when pooled with those of COMPACT-2. Indeed, they seem to corroborate our findings.
We wish to express concerns about the Trans20 longitudinal cohort study of transgender and gender diverse (TGD) youth from Melbourne’s Royal Children’s Hospital Gender Service (RCHGS) presented in the BMJ (Tollit et al BMJ Open 2019:9).
While we agree with the authors that in regard to the management of TGD youth there is ‘’urgent need for more evidence to ensure optimal medical and psychosocial interventionsi”, we have grave reservations about the ethical underpinnings and methodology of the study as described.
The Trans20 study aims to “document the natural history of gender diversity presenting in children”. It is not clear to us how the methodological design could allow observation of the ‘natural’ history of TGD youth when it intervenes in the developmental trajectories of all 600 expected participants. Given that a vast majority of young people who commence puberty blockers proceed to cross-sex hormonesii, it may well be the case that early intervention ‘locks’ a child into a persistent gender incongruence, closing them off to future choices in identity. We already do possess good data on the ‘natural history’ of gender confusion which shows that a majority of children desist at puberty and return to a gender identity congruent with their natal sexiii. Is this fact presented to concerned families?
The RCHGS adopts an exclusively gender-affirming model of care, offering psychosocial and biological interventions to children as young as 3. Although...
We wish to express concerns about the Trans20 longitudinal cohort study of transgender and gender diverse (TGD) youth from Melbourne’s Royal Children’s Hospital Gender Service (RCHGS) presented in the BMJ (Tollit et al BMJ Open 2019:9).
While we agree with the authors that in regard to the management of TGD youth there is ‘’urgent need for more evidence to ensure optimal medical and psychosocial interventionsi”, we have grave reservations about the ethical underpinnings and methodology of the study as described.
The Trans20 study aims to “document the natural history of gender diversity presenting in children”. It is not clear to us how the methodological design could allow observation of the ‘natural’ history of TGD youth when it intervenes in the developmental trajectories of all 600 expected participants. Given that a vast majority of young people who commence puberty blockers proceed to cross-sex hormonesii, it may well be the case that early intervention ‘locks’ a child into a persistent gender incongruence, closing them off to future choices in identity. We already do possess good data on the ‘natural history’ of gender confusion which shows that a majority of children desist at puberty and return to a gender identity congruent with their natal sexiii. Is this fact presented to concerned families?
The RCHGS adopts an exclusively gender-affirming model of care, offering psychosocial and biological interventions to children as young as 3. Although the Trans20 subjects are administered ostensibly different types of intervention, the therapeutic pathway in that model is a uniformly stepwise progression through the social and biological stages of transition.
The authors state that the information will be analysed under a “’clinical audit framework”. To us this study more closely resembles an ‘interventional’ clinical trial (lacking an untreated control group) rather than an observational study. We wonder if this distinction was made explicit to the participants and their families during the recruitment phase and formed part of the ‘informed consent’ process.
Our specific ethical concerns centre on whether the ‘informed consent’ offered to parents and their children reflect the rapid advances in complexity and uncertainty that have been reported in recent studiesiv,v,vi. It would be reasonable to expect a more detailed discussion of the consent process given the controversial nature of the treatments and the vulnerability of the participants. The report noted that consent was obtained through a ‘multi-step’ procedure. What does this mean? Are parents fully informed about the biological and psychological risks associated with delaying puberty through hormone blockers? Which aspects of gender dysphoria are and are not moderated by medical intervention? Are families dispassionately appraised of the high suicide rates and psychiatric morbidity post-transition? What supports, psychiatric or otherwise, are provided to subjects who, in the course of the study a) wish to revert to their natal gender (given the ostensibly fluid nature of gender) or b) are assessed as being dysphoric for reasons other than gender incongruence?
We welcome additional clinical and research data from the RCHGS Trans20 cohort study to clarify their ethical guidelines, including a detailed nature of the informed consent protocol so others might learn to maximize the safety/risk ratio for these vulnerable young people and their families.
Dr Roberto D’Angelo, FRANZCP
Dr Juan Carlos d’Abrera, FRANZCP
Dr George Halasz, FRANZCP
Dr Shirley Prager, FRANZCP
Dr Philip Morris, FRANZCP
Dr Ron Spielman, FRANZCP
Tollit, M.A., Pace, C.C., Telfer, M., Hoq, M., Bryson, J., Fulkoski, N., Cooper, C. and Pang, K.C., 2019. What are the health outcomes of trans and gender diverse young people in Australia? Study protocol for the Trans20 longitudinal cohort study. BMJ open, 9(11).
Steensma, T.D., Kreukels, B.P., de Vries, A.L. and Cohen-Kettenis, P.T., 2013. Gender identity development in adolescence. Hormones and behavior, 64(2), pp.288-297.
Singh, D., 2012. A follow-up study of boys with gender identity disorder (Doctoral dissertation, University of Toronto).
Littman, L., 2018. Rapid-onset gender dysphoria in adolescents and young adults: A study of parental reports. PloS one, 13(8), p.e0202330.
Chew, D., Anderson, J., Williams, K., May, T. and Pang, K., 2018. Hormonal treatment in young people with gender dysphoria: a systematic review. Pediatrics, 141(4)
Landen, M., 2019. Dramatic increase in adolescent gender dysphoria requires careful consideration. Lakartidningen, 116.
Dear Editor,
We read the excellent article by Warren and colleagues [1] with interest and agree wholeheartedly with the need for consolidated access to health records for clinicians across the healthcare ecosystem in the UK.
As junior doctors, we are often left with the laborious task of sourcing and amalgamating these disparate records for individual patients, with patients often surprised that we do not have access to all their information.
We note the authors recommend the common adoption of the same EHR software for trusts in the same region and the transfer of records between systems by open APIs. These aims are laudable, however, remain problematic:
1) Utilising the same EHR between NHS trusts does not necessarily guarantee any further ease of transfer than alternate EHRs; many trusts customise their EHR to their local preferences and hence implementations and data structures may vary significantly between trusts despite adopting the same EHR [2]. Further, even with the same systems, each trust will likely operate on differing domains, often requiring lengthy governance processes to facilitate transfer of records.
2) Open APIs such as Fast Healthcare Interoperability Resources (FHIR) [3] are available and implemented by the 3 major EHR vendors in the UK [4–6]. Despite this, exchange of records between different NHS trust systems remains limited.
The Summary Care Record (SCR) was initially intended as a repository of essential medic...
Dear Editor,
We read the excellent article by Warren and colleagues [1] with interest and agree wholeheartedly with the need for consolidated access to health records for clinicians across the healthcare ecosystem in the UK.
As junior doctors, we are often left with the laborious task of sourcing and amalgamating these disparate records for individual patients, with patients often surprised that we do not have access to all their information.
We note the authors recommend the common adoption of the same EHR software for trusts in the same region and the transfer of records between systems by open APIs. These aims are laudable, however, remain problematic:
1) Utilising the same EHR between NHS trusts does not necessarily guarantee any further ease of transfer than alternate EHRs; many trusts customise their EHR to their local preferences and hence implementations and data structures may vary significantly between trusts despite adopting the same EHR [2]. Further, even with the same systems, each trust will likely operate on differing domains, often requiring lengthy governance processes to facilitate transfer of records.
2) Open APIs such as Fast Healthcare Interoperability Resources (FHIR) [3] are available and implemented by the 3 major EHR vendors in the UK [4–6]. Despite this, exchange of records between different NHS trust systems remains limited.
The Summary Care Record (SCR) was initially intended as a repository of essential medical information about patients (including primary care visits and hospital correspondence) accessible across healthcare settings, much as the authors aspire for [7]. However, its scope has been downscaled to only include medication information for the majority of patients, with patients having to opt in to the sharing of their whole medical records as held by their general practitioner [8].
The majority of patients and general practitioners are not aware of this additional functionality and hence only a small minority of patients have their full medical records accessible through the SCR for secondary care services, although the basic SCR is available for over 55 million patients (96% of the population) in England [9].
Since general practitioners have access to patients’ complete medical records, with information retrieved from secondary care correspondence (the latter often transmitted electronically, near instantaneously, from secondary care EHRs), it makes sense to share this whole record as ‘additional information’ in the SCR by default, with the option to opt-out.
We believe the public’s attitudes to electronic records and sharing of medical information have changed dramatically since the inception of SCR and the NHS Programme for IT, where the internet and EHRs were relatively nascent. These reservations largely led to the shuttering of the intended functionality of the SCR. However, in the present day, with technology so ubiquitous, perceptions have shifted and there appears to be an expectation that there is on demand access to information, including medical information by clinicians.
We therefore believe in order to best achieve the aims outlined by Leigh and colleagues, we need to make the SCR opt-out for additional information. To achieve this would no doubt be challenging and would require surveying public and clinician opinion as well as support at a central government level. The new Local Health and Care Record initiative by the government is a step in the right direction [10] but will be significantly more complex to achieve and will likely have similar issues of interoperability between regions.
We believe expanding the use of the SCR is the most realistic, simplest and most cost-effective method of realising the vision of a connected NHS.
In our previous response we listed a number of differences between the study by Jensen et al.[1] and the studies by Sørup et al.[2, 3]. We thank Jensen et al. for providing the estimates for a restricted cohort of children who received 2 doses of DTP before 11 months of age (Table 1: https://bmjopen.bmj.com/pages/wp-content/uploads/sites/7/2019/11/table-1...). However,
restriction of the cohort to children with 2 DTP vaccines before 11 months of age only removes a limited part of the differences we mentioned; hence, the results in Table 1 are still incomparable to the previous studies by Sørup et al.
Jensen et al. included the 2DTP+MMR group in the modelling of effects (which Sørup et al. did not), and they did not analyse the data by type of infection, by sequence of vaccinations, and by the many confounders we had used. Since we specifically limited our studies to the period before PCV was part of the routine immunization programme, it should be noted that Jensen et al include many years where PCV was used (2007-2016). The introduction of PCV, a vaccine against respiratory infections, may have eliminated the need for some of the beneficial non-specific effects of MMR.
Rather than testing something else, finding something else, and concluding that previous studies testing and finding different things were flawed, the fruitful way forward would be to investigate the...
In our previous response we listed a number of differences between the study by Jensen et al.[1] and the studies by Sørup et al.[2, 3]. We thank Jensen et al. for providing the estimates for a restricted cohort of children who received 2 doses of DTP before 11 months of age (Table 1: https://bmjopen.bmj.com/pages/wp-content/uploads/sites/7/2019/11/table-1...). However,
restriction of the cohort to children with 2 DTP vaccines before 11 months of age only removes a limited part of the differences we mentioned; hence, the results in Table 1 are still incomparable to the previous studies by Sørup et al.
Jensen et al. included the 2DTP+MMR group in the modelling of effects (which Sørup et al. did not), and they did not analyse the data by type of infection, by sequence of vaccinations, and by the many confounders we had used. Since we specifically limited our studies to the period before PCV was part of the routine immunization programme, it should be noted that Jensen et al include many years where PCV was used (2007-2016). The introduction of PCV, a vaccine against respiratory infections, may have eliminated the need for some of the beneficial non-specific effects of MMR.
Rather than testing something else, finding something else, and concluding that previous studies testing and finding different things were flawed, the fruitful way forward would be to investigate the reasons for the apparently different results.
As it stands now Jensen et al.’s negative control outcome “hospitalisations for accidents” indicates that 3DTP+MMR is associated with an aHR=0.83 (0.80-0.86). Corrected for this level of residual confounding, MMR was associated with an 11% (95% CI: 7-15%) increase in the risk of infectious disease hospitalisation (0.92 (0.91-0.94)/0.83 (0.80-0.86)). This seems unlikely and implausible as such negative effects of MMR have not been noted before. Hence, the most likely explanation for the apparently divergent results is that Jensen et al. has constructed a data set with a lot of residual confounding.
1. Jensen, A., P.K. Andersen, and L.G. Stensballe, Early childhood vaccination and subsequent mortality or morbidity: are observational studies hampered by residual confounding? A Danish register-based cohort study. BMJ Open, 2019. 9(9): p. e029794.
2. Sorup, S., et al., Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. Jama, 2014. 311(8): p. 826-35.
3. Sorup, S., et al., Measles-mumps-rubella vaccination and respiratory syncytial virus-associated hospital contact. Vaccine, 2015. 33(1): p. 237-45.
Letter to editor:
We read with interest the article by Zhang et al. [1], in which they concluded that total hip bone mineral density was correlated with cardio ankle vascular index (CAVI). However, some common mistakes can happen in the studies using CAVI as a marker of arterial stiffness. First, Pearson’s correlation between this marker and other continuous variables should be considered after testing both variables for normality. Normality of the variables had been proposed as an assumption for the Pearson’s correlation analysis [2], if this assumption is not met, Spearman’s correlation should be performed after categorization of the continuous variables.
Second point that is essential in evaluation of CAVI is the effects of age on CAVI. Age has been proved to be largely correlated to CAVI and many studies tried to make reference values for CAVI in different age groups. Namekata et al. [3] provided reference values which can be used to categorize CAVI in the study individuals. Although Zhang et al. [1] controlled for age in the multiple linear regression, using reference values of CAVI in every individual could completely change the results and conclusions of their study. Although in the study of Zhange et al. [1] we can see the biggest correlation (r=0.631, P<0.001) between age and CAVI, correlation of age with other variables cannot be seen and there is a possibility that age and bone mineral density is also high. So, conclusions about the independent as...
Letter to editor:
We read with interest the article by Zhang et al. [1], in which they concluded that total hip bone mineral density was correlated with cardio ankle vascular index (CAVI). However, some common mistakes can happen in the studies using CAVI as a marker of arterial stiffness. First, Pearson’s correlation between this marker and other continuous variables should be considered after testing both variables for normality. Normality of the variables had been proposed as an assumption for the Pearson’s correlation analysis [2], if this assumption is not met, Spearman’s correlation should be performed after categorization of the continuous variables.
Second point that is essential in evaluation of CAVI is the effects of age on CAVI. Age has been proved to be largely correlated to CAVI and many studies tried to make reference values for CAVI in different age groups. Namekata et al. [3] provided reference values which can be used to categorize CAVI in the study individuals. Although Zhang et al. [1] controlled for age in the multiple linear regression, using reference values of CAVI in every individual could completely change the results and conclusions of their study. Although in the study of Zhange et al. [1] we can see the biggest correlation (r=0.631, P<0.001) between age and CAVI, correlation of age with other variables cannot be seen and there is a possibility that age and bone mineral density is also high. So, conclusions about the independent association of CAVI and bone mineral density is further questionable.
References
1. Zhang, M., et al., Links between arterial stiffness and bone mineral density in middle-aged and elderly Chinese individuals: a cross-sectional study. BMJ Open, 2019. 9(8): p. e029946.
2. Hazra, A. and N. Gogtay, Biostatistics Series Module 6: Correlation and Linear Regression. Indian J Dermatol, 2016. 61(6): p. 593-601.
3. Namekata, T., et al., Establishing baseline criteria of cardio-ankle vascular index as a new indicator of arteriosclerosis: a cross-sectional study. 2011. 11(1): p. 51.
We thank Demmler and colleagues for their reply to our concerns (dated 29th November 2019). In particular we appreciate the analysis required to demonstrate that the Joint Hypermobility Syndrome (JHS) and Ehlers-Danlos syndromes (EDS) cohorts in their study shared similar characteristics across the 35 Read chapter categories. This is a valuable observation of itself.
Demmler and colleagues say in their reply that we ‘asserted that diagnosed JHS is known to be common’. We assume they have misconstrued our opening comments about combining common with rare conditions. We used the words ‘common’ and ‘diagnosed JHS’ to describe their findings, and based on the prevalence of ‘diagnosed JHS’ in the population they studied. We recognise that this study is the first to directly report a healthcare record-based population prevalence for JHS and a healthcare record-based population prevalence for EDS.
We read that the authors agree with our comments that it is not possible to know what proportion of people who met the Brighton criteria for JHS also meet the 2017 hEDS criteria, and, that the authors agree that further studies are required to determine how common hypermobility spectrum disorder (HSD), hypermobile EDS (hEDS), and other forms of EDS are.
We appreciate that the authors did not “seek to remove the protected ‘rare’ status from all subtypes of EDS”, and that they “regret if their work has been misquoted on social media”. Demmler et al. also reply that...
We thank Demmler and colleagues for their reply to our concerns (dated 29th November 2019). In particular we appreciate the analysis required to demonstrate that the Joint Hypermobility Syndrome (JHS) and Ehlers-Danlos syndromes (EDS) cohorts in their study shared similar characteristics across the 35 Read chapter categories. This is a valuable observation of itself.
Demmler and colleagues say in their reply that we ‘asserted that diagnosed JHS is known to be common’. We assume they have misconstrued our opening comments about combining common with rare conditions. We used the words ‘common’ and ‘diagnosed JHS’ to describe their findings, and based on the prevalence of ‘diagnosed JHS’ in the population they studied. We recognise that this study is the first to directly report a healthcare record-based population prevalence for JHS and a healthcare record-based population prevalence for EDS.
We read that the authors agree with our comments that it is not possible to know what proportion of people who met the Brighton criteria for JHS also meet the 2017 hEDS criteria, and, that the authors agree that further studies are required to determine how common hypermobility spectrum disorder (HSD), hypermobile EDS (hEDS), and other forms of EDS are.
We appreciate that the authors did not “seek to remove the protected ‘rare’ status from all subtypes of EDS”, and that they “regret if their work has been misquoted on social media”. Demmler et al. also reply that they chose to recognise HSD as a possible diagnosis for an unknown proportion of the JHS patients. This concurs with our original point that the proportion is unknown. By the same reasoning, the proportion of hEDS would be unknown. Given this we have not changed our position in questioning why the authors stated “we conclude that EDS/HSD are not rare conditions”, when the term EDS includes these rare conditions and the authors could not know how rare or otherwise each of HSD and hEDS are.
We also agree with Demmler et al. that HSD and hEDS individuals can have the same complex medical conditions. This was not something that we questioned. We note Demmler et al. in their reply cite our authorship (1) for which there is an associated editorial (2).
The authors also state that experts in the field considered JHS and EDS hypermobile type (EDS-HT) to be clinically indistinguishable. As it reads this statement is correct. However, it is not a universal truth. Not all cases of JHS are indistinguishable from EDS-HT. When Kirk, Ansell, and Bywaters published their observations and introduced the term Hypermobility Syndrome (3), they also described that their patient population had no evidence of any other features to suggest a hereditary connective tissue disorder (HDCT) such as EDS or Marfan syndrome.
Hypermobility syndrome (HS) was subsequently subsumed by the term JHS. However, the Brighton criteria for JHS included other signs that were more suggestive of an HDCT (4). Ensuing publications questioned whether these additional features were more typical of the hypermobile type of EDS (Villefranche criteria) (5), and, reported inconsistency between experts in their use of diagnostic terminology. The way the criteria was structured was such that the diagnosis JHS could include individuals previously described as HS, individuals with JHS by the Brighton criteria but not having sufficient features of an HDCT, and individuals with findings more typical of the hypermobile type of EDS (then described as JHS/EDS-HT) (4, 6-9).
In bringing together the diagnostic features of JHS/EDS-HT and the hypermobile type of EDS, the authors of the 2017 hEDS criteria recognized the need for additional descriptive diagnoses because not all individuals with JHS had signs consistent with a diagnosis of hEDS. Tinkle et al. wrote in their criteria paper (10):
"It is, therefore, the consensus of the authors on behalf of the International Consortium on the Ehlers–Danlos Syndromes, based on the present state of our knowledge, that the two conditions [of JHS, and hEDS] are part of the same clinical spectrum ranging from apparently symptomatic GJH to individuals fitting the new diagnostic criteria for hEDS.
Grouping all phenotypes comprised in this spectrum under the same heading may be misleading on both nosologic and therapeutic perspectives.
For all these individuals not showing a sufficiently convincing hEDS phenotype, some alternative labels within the above‐mentioned spectrum are presented elsewhere".
By ‘elsewhere’ they were referring to the paper by Castori et al. (11), that describes the framework for the term Hypermobility Spectrum Disorders.
In our opinion, which we re-iterate, data that is derived from studies of JHS would require researchers to either go back and re-diagnose the subgroups of JHS if they are to report the study as HSD and hEDS, or model assumptions with regard to the relative proportions of cases that might be assumed to be HSD or hEDS.
While still respecting the relationships between HSD and hEDS as a spectrum with definable boundaries based on criteria, researchers are able to study each individual condition, or both in parallel looking for commonality, drawing together evidence for similarity but without losing what might make one condition different from the other. We believe this is an important principle that is lost if conditions are combined together from the outset.
With regard to prevalence studies, in our opinion it is more informative that the prevalence of hEDS is cited separate from that of other forms of EDS, not only to clearly present the prevalence of hEDS per se, but also avoid statements about EDS as a whole that might mis-represent the rare and ultra-rare nature of most of its variants.
Finally, having worked with thousands of patients between us, we fully appreciate, and agree with Demmler et al., that these conditions require more recognition, and better understanding of the nature, and efficacy of treatment. In this regard we hope that our comments are helpful with regard to the use of terminology.
We are grateful to BMJ Open for the opportunity to have shared our opinion, and for Demmler and colleagues' reply, and we draw our commentary to a close,
References.
1. Copetti M, Morlino S, Colombi M, et al. Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients. Rheumatology. 2019;58:1722–1730
2. Hakim AJ. Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder, Rheumatology (Oxford). 2019 Oct 1;58(10):1705-1706
3. Kirk JA, Ansell BM, Bywaters EG. The hypermobility syndrome. Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis. 1967;26:419-425
4. Grahame R, Bird HA, and Child A. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). Journal of Rheumatology. 2000;27(7):1777-1779
5. Beighton P, De Paepe PA, Steinmann B, Tsipouras P, and Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers Danlos National Foundation (USA) and Ehlers Danlos Support Group (UK). Am J Med Genet. 1998;77(1):31-37
6. Remvig L, Jensen DV, Ward RC. Are diagnostic criteria for general joint hypermobility and benign joint hypermobility syndrome based on reproducible and valid tests? A review of the literature.J Rheumatol. 2007;Apr;34(4): 798-803
7. Remvig L, Flycht L, Christensen KB, Juul-Kristensen B. Lack of consensus on tests and criteria for generalized joint hypermobility, Ehlers–Danlos syndrome: Hypermobile type and joint hypermobility syndrome. Am J Med Genet A. 2014:Mar;164A(3);591-596
8. Tinkle BT, Bird HA, Grahame R, et al. The lack of clinical distinction between the hypermobility type of Ehlers-Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A. 2009; Nov;149A(11):2368-2370
9. Castori M, Dordoni C, Valiante M, et al. Nosology and inheritance pattern(s) of joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type: a study of intrafamilial and interfamilial variability in 23 Italian pedigrees. Am J Med Genet A. 2014 Dec;164A(12):3010-3020
10. Tinkle B, Castori M, Berglund, B, et al. Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):48-69
11. Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet C Semin Med Genet. 2017;175C:148-157
We hereby write to inform the readers of changes to the statistical plan for our clinical trial MAGiCAL-CKD, which we have previously published in BMJ Open. At the time of writing, the trial is still on-going and the data set has not been unblinded. Thus, any changes to the statistical plan at this time will not compromise the integrity of the trial design.
The purpose of the MAGiCAL-CKD trial is to examine the effect of magnesium (Mg) supplementation on coronary artery calcification (CAC) score in patients with chronic kidney disease. The original statistical plan was to analyse the change in CAC score from week 0 to week 52 (delta CAC score) and compare the delta CAC score between the two treatment groups. The choice of delta CAC as the primary endpoint (and not the between-group difference in CAC score at week 52) was made due to the potential for an imbalance in CAC score between the two treatment groups at week 0. The delta CAC was thought to better account for any baseline imbalance. However, since the publication of the trial protocol we have become aware that this methodology is flawed and that the correct analysis is to perform an analysis of covariance (ANCOVA) of CAC score between the two treatment groups at week 52 adjusted for CAC score, age and prevalent diabetes mellitus (yes/no) at week 0. Therefore, the ANCOVA test will be applied to analyse the primary endpoint. Essentially, we are examining the same scientific question, but using better methodology...
We hereby write to inform the readers of changes to the statistical plan for our clinical trial MAGiCAL-CKD, which we have previously published in BMJ Open. At the time of writing, the trial is still on-going and the data set has not been unblinded. Thus, any changes to the statistical plan at this time will not compromise the integrity of the trial design.
The purpose of the MAGiCAL-CKD trial is to examine the effect of magnesium (Mg) supplementation on coronary artery calcification (CAC) score in patients with chronic kidney disease. The original statistical plan was to analyse the change in CAC score from week 0 to week 52 (delta CAC score) and compare the delta CAC score between the two treatment groups. The choice of delta CAC as the primary endpoint (and not the between-group difference in CAC score at week 52) was made due to the potential for an imbalance in CAC score between the two treatment groups at week 0. The delta CAC was thought to better account for any baseline imbalance. However, since the publication of the trial protocol we have become aware that this methodology is flawed and that the correct analysis is to perform an analysis of covariance (ANCOVA) of CAC score between the two treatment groups at week 52 adjusted for CAC score, age and prevalent diabetes mellitus (yes/no) at week 0. Therefore, the ANCOVA test will be applied to analyse the primary endpoint. Essentially, we are examining the same scientific question, but using better methodology. The ANCOVA test will likewise be used to examine the between-group differences at week 52 in blood levels of Mg, phosphate, ionised calcium, parathyroid hormone, fibroblast growth factor 23, estimated glomerular filtration rate (eGFR), potassium, and calcification propensity; urine levels of Mg and phosphate; carotid-femoral pulse wave velocity and pulse wave analysis; and bone mineral density. Linear mixed models with repeated measures will be used to analyse changes in blood Mg, phosphate, ionised calcium, parathyroid hormone, eGFR, and potassium; as well as urine Mg and phosphate.
In addition, we wish to investigate whether certain subgroups affect the treatment effect of Mg supplementation on CAC score. The prespecified subgroups are: 1) prevalent diabetes mellitus at week 0; 2) CAC score = 0 versus CAC score > 0 at week 0; and 3) tertiles of serum calcification propensity at week 0. These subgroups will be analysed for heterogeneity of treatment effect and will be presented as Forrest plots with p-values for treatment interaction.
Lastly, in order to examine whether Mg supplementation affects various clinical outcomes stratified Cox proportional hazards models and Kaplan-Meier time-to-event analyses will be used to examine the incidence of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, new-onset heart failure, hospitalisation for heart failure, limb amputation or revascularisation due to peripheral arterial occlusion) after 1 and 5 years follow-up with treatment group as a fixed factor and additional covariates at week 0 (age, gender, CAC score, prevalent diabetes mellitus, and eGFR). Additional models will be used to examine the incidence of all-cause mortality with treatment group as a fixed factor and additional covariates at week 0 (age, gender, CAC score, prevalent diabetes mellitus, prevalent cardiovascular disease, and eGFR) as well as the incidence of end-stage kidney disease (dialysis treatment for more than 3 months, kidney transplantation or death from renal disease) with treatment group as a fixed factor and additional covariates at week 0 (age, gender, 24-hour urine protein, prevalent diabetes mellitus, and eGFR).
The healthcare environment in which people with intellectual disabilities (PWID) receive care and are prescribed medication is increasingly complex. PWID and their carers know the complexity of their needs, and they alone know the real gaps in healthcare that can occur in services provided to them. It is important that PWID are included in decisions about their own healthcare of which medication use is a major component. Exercising autonomy in the medication use process can be difficult and may not ensure the highest quality healthcare for PWID who usually are dependent on others for many aspects their care and access to care (1).
In an Irish qualitative study where 6 people with intellectual disabilities were interviewed about their medicines ,one participant prescribed Stelazine described that when he started taking it his ‘strength went down’ and ‘it was hard to do things’. (Alex). His concerned parent reported being ‘unheard’ during encounters with the prescriber (2).
Diverse interventions offer promising approaches to improving medication adherence for chronic conditions, particularly for the short term. Evidence on whether these approaches have broad applicability for clinical conditions and populations is limited, as is evidence regarding long-term medication adherence or health outcomes.
PWID can provide valuable insight into the medication use process.
Patients who are given and supported to use information to make decisions a...
The healthcare environment in which people with intellectual disabilities (PWID) receive care and are prescribed medication is increasingly complex. PWID and their carers know the complexity of their needs, and they alone know the real gaps in healthcare that can occur in services provided to them. It is important that PWID are included in decisions about their own healthcare of which medication use is a major component. Exercising autonomy in the medication use process can be difficult and may not ensure the highest quality healthcare for PWID who usually are dependent on others for many aspects their care and access to care (1).
In an Irish qualitative study where 6 people with intellectual disabilities were interviewed about their medicines ,one participant prescribed Stelazine described that when he started taking it his ‘strength went down’ and ‘it was hard to do things’. (Alex). His concerned parent reported being ‘unheard’ during encounters with the prescriber (2).
Diverse interventions offer promising approaches to improving medication adherence for chronic conditions, particularly for the short term. Evidence on whether these approaches have broad applicability for clinical conditions and populations is limited, as is evidence regarding long-term medication adherence or health outcomes.
PWID can provide valuable insight into the medication use process.
Patients who are given and supported to use information to make decisions about their care
• are able to manage their long-term conditions more effectively
• use healthcare services less often than patients who have not been given information
• choose less invasive/less expensive treatment options
• have fewer repeat consultations with health professionals
• have fewer unscheduled admissions to hospital, and lower rates of readmission
• comply better with medicines regimes - fewer wasted drugs.
Information Prescriptions give people with long-term conditions or care needs reliable, accurate information to help them manage their health more effectively and live more independently. They contain information, and signposts to further sources of advice and support, e.g. local support groups. They are a little like a medicine prescription i.e. a medicines prescription tells a patient what drugs they need to take; an information prescription gives them information to help them cope on a daily basis.
It is important to train health care professionals in meeting the communication needs of PWID at undergraduate and postgraduate level and encourage involvement by PWID.
Pharmacists have a role to play.
(1) Flood, Bernadette .PhD, MPSI. Oral presentation HIRC Trinity College Dublin, Nov 2016. People with intellectual disabilities living in the community. What can they tell us about adherence to medication in this vulnerable population?
(2) Bernadette Flood, 'The specialist pharmacist and quality indicators of medication use in the care of people with intellectual disabilities and behaviour disorders', [thesis], Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences, 2016, pp.566
The primary purpose of this response letter is to update the protocol to revise the sample size of the Compass Trial.
Summary
Compass is a randomised controlled trial, operating alongside the Australian National Cervical Screening Program (NCSP). Under the auspices of the Independent Data Safety Monitoring Committee (IDSMC) and Scientific Advisory Committee (SAC) we have performed a re-analysis of our original estimate of the total trial sample size. This was prompted by two factors: (1) impact of the NCSP transition to primary HPV screening and (2) emergence of new evidence relevant to the sample size calculation. With consideration to the resource implications of the renewed program on trial recruitment and acknowledging that the original sample size of 121,000 women for the main trial was calculated in 2014 (prior to the emergence of new relevant evidence) the trial sample size was re-estimated.
The sample size recalculation has resulted in a reduced recruitment target for the cohort of women in Compass Trial who were age-eligible for publicly funded HPV vaccination in Australia (the younger cohort) from 84,700 to 40,000 women; consequently the total recruitment target has been revised from 121,000 to 76,300. The updated sample size estimate has been approved by the Human Research Ethics Committee and is reflected in the trial registration (ClinicalTrials.gov Identifier: NCT02328872).
(1) Impact of the NCSP transition to primary HPV scree...
Show MoreThanks to Rydahl et al. for yet an attempt to question a more offensive post-term induction practice to have a main responsibility for the impressing reduction in stillbirths in Denmark (1). The more offensive induction practice was gradually implemented in Denmark through this century but accelerated by the National recommendation in 2010-2011 to induce post-term women so to ensure delivery before 42 gestational weeks (GW).
The following comments assume that the data presented by Rydahl et al. are correct, we are currently looking at the same issue and the same data.
First what we agree on:
• There has from 2000 to 2012 been a substantial decrease in stillbirths in Denmark among women pregnant beyond 41+3 GW. The reduction was from 2.6 to <0.5 stillbirths per 1000 delivered, a reduction of at least 80%. Shouldn’t we start by congratulating each other for this impressing National achievement.
• During the same period has the proportion of induced deliveries increased for women going beyond 41+3 GW from 25% to around 65%.
• Despite this dramatic change in induction practice, both Caesarean section rates, low Apgar scores, and birth augmentation have been almost stable.
• The proportion of instrumental births has decreased during the same period.
It is of course an important issue what caused the dramatic decrease in stillbirths over the last two decades in Denmark. We have previously published evidence arguing that the more offe...
Show MoreWe read with interest this paper reporting the results of the ROMPA trial on the efficacy of Coupled Plasma Filtration and Adsorption (CPFA) in reducing mortality in patients with septic shock. The trial was prematurely closed, after we informed the investigators of ROMPA that we had stopped our COMPACT-2 trial, designed on the same topic, for reasons of futility. COMPACT-2 (NCT01639664), whose protocol inspired ROMPA, was prompted by a pre-planned subgroup analysis coming from the overall negative COMPACT trial, suggesting that CPFA might have been effective, had a high volume of plasma been treated.
Show MoreThe first planned interim analysis of COMPACT-2, aimed at assessing the feasibility of the technique, revealed a number of early deaths during CPFA. This induced the External Data and Safety Monitoring Committee (EDSMC) to request an unplanned interim analysis of safety. Such analysis, performed on the 113 recruited patients, showed significantly higher mortality in the CPFA group compared to controls, both at 3 days from randomization and at the 90-day survival analysis. We have now completed the clinical review of each recruited patient, performed through site visits by a team of independent experts, and plan to submit the manuscript to a scientific journal.
In the meantime, we would like to clarify a couple of aspects related to our trial that were misreported in the present article and to comment on some sections of the paper. First, COMPACT-2 was not stopped...
We wish to express concerns about the Trans20 longitudinal cohort study of transgender and gender diverse (TGD) youth from Melbourne’s Royal Children’s Hospital Gender Service (RCHGS) presented in the BMJ (Tollit et al BMJ Open 2019:9).
While we agree with the authors that in regard to the management of TGD youth there is ‘’urgent need for more evidence to ensure optimal medical and psychosocial interventionsi”, we have grave reservations about the ethical underpinnings and methodology of the study as described.
The Trans20 study aims to “document the natural history of gender diversity presenting in children”. It is not clear to us how the methodological design could allow observation of the ‘natural’ history of TGD youth when it intervenes in the developmental trajectories of all 600 expected participants. Given that a vast majority of young people who commence puberty blockers proceed to cross-sex hormonesii, it may well be the case that early intervention ‘locks’ a child into a persistent gender incongruence, closing them off to future choices in identity. We already do possess good data on the ‘natural history’ of gender confusion which shows that a majority of children desist at puberty and return to a gender identity congruent with their natal sexiii. Is this fact presented to concerned families?
The RCHGS adopts an exclusively gender-affirming model of care, offering psychosocial and biological interventions to children as young as 3. Although...
Show MoreDear Editor,
Show MoreWe read the excellent article by Warren and colleagues [1] with interest and agree wholeheartedly with the need for consolidated access to health records for clinicians across the healthcare ecosystem in the UK.
As junior doctors, we are often left with the laborious task of sourcing and amalgamating these disparate records for individual patients, with patients often surprised that we do not have access to all their information.
We note the authors recommend the common adoption of the same EHR software for trusts in the same region and the transfer of records between systems by open APIs. These aims are laudable, however, remain problematic:
1) Utilising the same EHR between NHS trusts does not necessarily guarantee any further ease of transfer than alternate EHRs; many trusts customise their EHR to their local preferences and hence implementations and data structures may vary significantly between trusts despite adopting the same EHR [2]. Further, even with the same systems, each trust will likely operate on differing domains, often requiring lengthy governance processes to facilitate transfer of records.
2) Open APIs such as Fast Healthcare Interoperability Resources (FHIR) [3] are available and implemented by the 3 major EHR vendors in the UK [4–6]. Despite this, exchange of records between different NHS trust systems remains limited.
The Summary Care Record (SCR) was initially intended as a repository of essential medic...
In our previous response we listed a number of differences between the study by Jensen et al.[1] and the studies by Sørup et al.[2, 3]. We thank Jensen et al. for providing the estimates for a restricted cohort of children who received 2 doses of DTP before 11 months of age (Table 1: https://bmjopen.bmj.com/pages/wp-content/uploads/sites/7/2019/11/table-1...). However,
Show Morerestriction of the cohort to children with 2 DTP vaccines before 11 months of age only removes a limited part of the differences we mentioned; hence, the results in Table 1 are still incomparable to the previous studies by Sørup et al.
Jensen et al. included the 2DTP+MMR group in the modelling of effects (which Sørup et al. did not), and they did not analyse the data by type of infection, by sequence of vaccinations, and by the many confounders we had used. Since we specifically limited our studies to the period before PCV was part of the routine immunization programme, it should be noted that Jensen et al include many years where PCV was used (2007-2016). The introduction of PCV, a vaccine against respiratory infections, may have eliminated the need for some of the beneficial non-specific effects of MMR.
Rather than testing something else, finding something else, and concluding that previous studies testing and finding different things were flawed, the fruitful way forward would be to investigate the...
Letter to editor:
Show MoreWe read with interest the article by Zhang et al. [1], in which they concluded that total hip bone mineral density was correlated with cardio ankle vascular index (CAVI). However, some common mistakes can happen in the studies using CAVI as a marker of arterial stiffness. First, Pearson’s correlation between this marker and other continuous variables should be considered after testing both variables for normality. Normality of the variables had been proposed as an assumption for the Pearson’s correlation analysis [2], if this assumption is not met, Spearman’s correlation should be performed after categorization of the continuous variables.
Second point that is essential in evaluation of CAVI is the effects of age on CAVI. Age has been proved to be largely correlated to CAVI and many studies tried to make reference values for CAVI in different age groups. Namekata et al. [3] provided reference values which can be used to categorize CAVI in the study individuals. Although Zhang et al. [1] controlled for age in the multiple linear regression, using reference values of CAVI in every individual could completely change the results and conclusions of their study. Although in the study of Zhange et al. [1] we can see the biggest correlation (r=0.631, P<0.001) between age and CAVI, correlation of age with other variables cannot be seen and there is a possibility that age and bone mineral density is also high. So, conclusions about the independent as...
We thank Demmler and colleagues for their reply to our concerns (dated 29th November 2019). In particular we appreciate the analysis required to demonstrate that the Joint Hypermobility Syndrome (JHS) and Ehlers-Danlos syndromes (EDS) cohorts in their study shared similar characteristics across the 35 Read chapter categories. This is a valuable observation of itself.
Demmler and colleagues say in their reply that we ‘asserted that diagnosed JHS is known to be common’. We assume they have misconstrued our opening comments about combining common with rare conditions. We used the words ‘common’ and ‘diagnosed JHS’ to describe their findings, and based on the prevalence of ‘diagnosed JHS’ in the population they studied. We recognise that this study is the first to directly report a healthcare record-based population prevalence for JHS and a healthcare record-based population prevalence for EDS.
We read that the authors agree with our comments that it is not possible to know what proportion of people who met the Brighton criteria for JHS also meet the 2017 hEDS criteria, and, that the authors agree that further studies are required to determine how common hypermobility spectrum disorder (HSD), hypermobile EDS (hEDS), and other forms of EDS are.
We appreciate that the authors did not “seek to remove the protected ‘rare’ status from all subtypes of EDS”, and that they “regret if their work has been misquoted on social media”. Demmler et al. also reply that...
Show MoreWe hereby write to inform the readers of changes to the statistical plan for our clinical trial MAGiCAL-CKD, which we have previously published in BMJ Open. At the time of writing, the trial is still on-going and the data set has not been unblinded. Thus, any changes to the statistical plan at this time will not compromise the integrity of the trial design.
Show MoreThe purpose of the MAGiCAL-CKD trial is to examine the effect of magnesium (Mg) supplementation on coronary artery calcification (CAC) score in patients with chronic kidney disease. The original statistical plan was to analyse the change in CAC score from week 0 to week 52 (delta CAC score) and compare the delta CAC score between the two treatment groups. The choice of delta CAC as the primary endpoint (and not the between-group difference in CAC score at week 52) was made due to the potential for an imbalance in CAC score between the two treatment groups at week 0. The delta CAC was thought to better account for any baseline imbalance. However, since the publication of the trial protocol we have become aware that this methodology is flawed and that the correct analysis is to perform an analysis of covariance (ANCOVA) of CAC score between the two treatment groups at week 52 adjusted for CAC score, age and prevalent diabetes mellitus (yes/no) at week 0. Therefore, the ANCOVA test will be applied to analyse the primary endpoint. Essentially, we are examining the same scientific question, but using better methodology...
The healthcare environment in which people with intellectual disabilities (PWID) receive care and are prescribed medication is increasingly complex. PWID and their carers know the complexity of their needs, and they alone know the real gaps in healthcare that can occur in services provided to them. It is important that PWID are included in decisions about their own healthcare of which medication use is a major component. Exercising autonomy in the medication use process can be difficult and may not ensure the highest quality healthcare for PWID who usually are dependent on others for many aspects their care and access to care (1).
In an Irish qualitative study where 6 people with intellectual disabilities were interviewed about their medicines ,one participant prescribed Stelazine described that when he started taking it his ‘strength went down’ and ‘it was hard to do things’. (Alex). His concerned parent reported being ‘unheard’ during encounters with the prescriber (2).
Diverse interventions offer promising approaches to improving medication adherence for chronic conditions, particularly for the short term. Evidence on whether these approaches have broad applicability for clinical conditions and populations is limited, as is evidence regarding long-term medication adherence or health outcomes.
PWID can provide valuable insight into the medication use process.
Patients who are given and supported to use information to make decisions a...
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