There is limited real-world evidence on how increasing use of treatment intensification in metastatic castration-sensitive prostate cancer (mCSPC) has influenced treatment decisions in metastatic castration-resistant prostate cancer (mCRPC). The study objective was to evaluate the impact of novel hormonal therapy (NHT) and docetaxel use in mCSPC on first-line treatment patterns among patients with mCRPC in 5 European countries and the United States (US).Physician-reported data on patients with mCRPC from the Adelphi Prostate Cancer Disease Specific Program were descriptively analyzed.n = 76) mostly received taxane chemotherapy in mCRPC (55%). Patients who had received taxane chemotherapy, or who did not receive taxane chemotherapy or NHT in mCSPC  mostly received NHT in mCRPC . In the US, patients who had received NHT, taxane chemotherapy, or neither in mCSPC  mostly received NHT in mCRPC . Two patients in Europe were rechallenged with the same NHT.A total of 215 physicians provided data on 722 patients with mCRPC. Across 5 European countries and the US, 65% and 75% of patients, respectively, received NHT, and 28% and 9% of patients, respectively, received taxane chemotherapy as first-line mCRPC treatment. In Europe, patients who had received NHT in mCSPC  setting influence choice of first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) across a diverse, real-world patient population in five European countries and the US. There is limited real-world evidence on how treatment decisions in metastatic castration-resistant prostate cancer (mCRPC) are influenced by the increasing use of treatment intensification  in metastatic castration-sensitive prostate cancer (mCSPC). The findings of this real-world study suggest that physicians in 5 European countries and the US considered previous treatments received in the mCSPC setting when making treatment decisions for their patients with mCRPC. As the use of intensified treatment in mCSPC increases and more treatment options become available in mCRPC, greater insight into optimal treatment sequencing will be required.1-20 Since approval in mCRPC, docetaxel and novel hormonal therapies (NHTs) are being administered earlier in the prostate cancer treatment continuum. Following the survival benefit shown in clinical trials,21-26 NHTs28 and docetaxel29 in Europe, and NHTs31 in the US, are now approved for use as intensified treatment in metastatic castration-sensitive prostate cancer (mCSPC). Although real-world US and Canadian studies show that most patients still do not receive intensified treatment in the mCSPC setting, there has been a trend toward increased treatment intensification in recent years.32-43The treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) has expanded over the past 2 decades since approval of the taxane chemotherapy, docetaxel, in 2004 in the United States US; .1-20 Sin44-46 These guidelines also recommend molecular sequencing when patients are refractory or non-responsive to androgen deprivation therapy (ADT) with docetaxel or NHT, to elucidate the next best course of action.44-46 There is evidence that molecular profiling could be used to further stratify patients with refractory mCRPC, and thus better inform treatment selection and sequencing.47American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO)/Society for Urologic Oncology (SUO), European Association of Urology (EAU), and European Society for Medical Oncology (ESMO) guidelines state that prior treatment sequencing should be considered when choosing treatment in mCRPC, and recommend a treatment with an alternative mechanism of action to previous therapies.48-50 Insight into optimal treatment sequencing is becoming increasingly important with the anticipated increased use of NHTs in the mCSPC setting and as further new treatment options become available. As such, the objective of this study was to evaluate whether treatments used in the mCSPC setting influence choice of first-line treatment in mCRPC across a diverse, real-world patient population in 5 European countries  and the US.Real-world evidence is important to inform our understanding of current mCRPC treatment patterns. However, the few studies that have been published on treatment sequencing in mCRPC tended to consider first-line and second-line mCRPC treatment only, without consideration for how treatment intensification in the mCSPC setting could influence treatment decisions in the mCRPC setting.51-53Data from the Prostate Cancer Disease Specific Program (DSP) were utilized and subsequently analyzed for the purpose of this study. The DSP is a point-in-time, physician-conducted extraction of medical chart data. The surveys are conducted in routine clinical practice, and the data collected describe patient demographics and clinical characteristics; and prostate cancer disease management including treatment history, the burden and impact of prostate cancer, and associated treatment effects from the perspective of the physician. The DSP methodology has been previously published and validated.Physicians in the UK, France, Germany, Spain, Italy, and the US reported information for their patients with metastatic prostate cancer attending a physician’s appointment between January and August 2020.A geographically diverse sample of physicians was identified by local fieldwork agents using physician panels and publicly available lists. All physicians self-identified as oncologists or urologists. All physicians had personal responsibility for prescribing decisions for patients with prostate cancer, and were seeing 2 or more patients with mCRPC (at time of data collection) and 2 or more patients with mCSPC per month.Patients included in this study were male, ≥18 years old, currently diagnosed with mCRPC, had never taken part in a clinical trial, and were receiving systemic drug treatment for metastatic prostate cancer (any line). Patients who had orchiectomy alone were not included in this analysis. All patients who had a drug treatment for mCRPC initiated between 2016 and 2020 were included in this analysis. All patients in this analysis progressed from mCSPC to mCRPC.Participating physicians completed an attitudinal survey with questions on physician and practice characteristics. Following this, physicians completed detailed patient record forms (PRFs) for their next 4 eligible, adult patients treated for mCRPC. The number of patients per physician was limited as such to allow for a varied representation. The PRFs collected detailed information on patient and clinical characteristics, patient management, and treatment history at the time of data collection. Ethnicity was identified by physicians and was not self-identified by patients.54The Eastern Cooperative Oncology Group Performance Status Scale (ECOG) was used to assess performance status, which scores from 0 (fully active) to 4 (completely disabled).First-line mCRPC treatments were described overall and stratified by treatments received in the mCSPC setting. Patients were classed as either treated with no NHT and no taxane chemotherapy in mCSPC; treated with taxane chemotherapy in mCSPC ; or treated with a NHT  in mCSPC. mCSPC treatment groups were allowed to overlap .The Adelphi DSP was submitted to and obtained exemption from the Western Institutional Review Board, study protocol number AG8741.55 and as such it did not require ethics committee approval. Each survey was performed in full accordance with relevant legislation at the time of data collection, including the US Health Insurance Portability and Accountability Act 1996,56 and the Health Information Technology for Economic and Clinical Health Act.57 Data were collected in such a way that patients and physicians could not be identified directly.Data collection was undertaken in line with European Pharmaceutical Marketing Research Association guidelinesData were analyzed descriptively using IBM SPSS Data Collection Survey Reporter Version 6 or later . For continuous variables, we reported mean and SD, and/or median and range. For categorical variables, frequency and percentage distribution were reported.Across all countries, 215 physicians (187 across 5 European countries and 28 in the US) provided data on 722 patients (606 across 5 European countries and 116 in the US) with mCRPC. Across the 5 European countries, at the time of data collection, the majority (93%) of patients were White/Caucasian, with a median (range) age of 72 (45-90) years . Approxin = 606), NHT was the most common first-line treatment . Abiraterone was administered more frequently than enzalutamide as first-line treatment in mCRPC . Apalutamide was administered to 1% (n = 4) of all patients in Europe as first-line treatment in mCRPC. Taxane chemotherapy was used as first-line treatment for 28% (n = 170) of patients (20% docetaxel [n = 124] and 8% cabazitaxel [n = 46]). Only 5% of patients (n = 30) received ADT with or without a first-generation nonsteroidal anti-androgen (NSAA) as first-line treatment in mCRPC  initiated first-line mCRPC treatment in 2020. In the total analysis population (in mCRPC .n = 434) received no NHT and no taxane chemotherapy. Most of these patients  received an NHT  as first-line treatment in mCRPC (n = 76), docetaxel was the most common first-line mCRPC treatment . Use of the same NHT drug in the mCSPC setting and as first-line treatment in mCRPC was minimal (n = 2). For patients who received a taxane chemotherapy , the most common first-line mCRPC treatments were abiraterone , enzalutamide , and cabazitaxel . Apalutamide was administered to <1% (n = 2) of all patients in Europe in the mCSPC setting.Abiraterone was administered more frequently than enzalutamide as treatment in the mCSPC setting (9% [n = 116), NHT was the most common first-line treatment in mCRPC . Enzalutamide was received more frequently than abiraterone as first-line mCRPC treatment . Apalutamide was received by 3% (n = 3) of all US patients as first-line mCRPC treatment. The numbers of patients administered taxane chemotherapy (docetaxel) or ADT with or without NSAA as first-line treatment in mCRPC were similar   initiated first-line mCRPC treatment in 2020. In the total analysis population (ctively) .n = 72) received no NHT and no taxane chemotherapy. Subsequently, most of these patients  were administered an NHT  as first-line treatment in mCRPC. In the mCSPC setting, 10% of patients (n = 12) received a taxane chemotherapy (mainly docetaxel) and 28% of patients (n = 32) received an NHT. Among these patients, an NHT was the most common first-line treatment in mCRPC . All patients treated with an NHT in the mCSPC setting went on to receive a different NHT drug as first-line treatment in mCRPC than the NHT used in mCSPC . Apalutamide was administered to 2% (n = 2) of all US patients in the mCSPC setting.Abiraterone was administered more frequently to treat mCSPC than enzalutamide (15% [n = 564), Afro-Caribbean patients (n = 17), and patients of other ethnicities (n = 25), 67% (n = 380), 65% (n = 11), and 60% (n = 15), respectively, were administered an NHT . In the US, of White/Caucasian patients (n = 71), African American patients (n = 29), and patients of other ethnicities (n = 16), 77% (n = 55), 72% (n = 21), and 69% (n = 11), respectively, were administered an NHT  received an NHT . Of 77 urologist-treated patients in Europe, 69% (n = 53) received an NHT . Of 96 oncologist-treated patients in the US, 74% (n = 71) received an NHT . Of 20 urologist-treated patients in the US, 80% (n = 16) received an NHT  received an NHT. Of 41 patients with commercial insurance, 83% (n = 34) received an NHT  as first-line treatment in mCRPC. Of 62 patients in Medicare, 71%  of oncologist-treated patients and 73% (n = 56) of urologist-treated patients received no NHT and no taxane chemotherapy. In the US, 56% (n = 54) of oncologist-treated patients and 90% (n = 18) of urologist-treated patients received no NHT and no taxane chemotherapy  looked at 2 cohorts of mCRPC treatment, reflecting the more current and prior treatment landscapes: patients treated between 2006 and 2010, and patients treated between 2011 and 2016.61 Fifty-eight percent of patients went on to receive a hormonal therapy following docetaxel. It was also found that treatment patterns were influenced by region, with hormonal therapy used more and chemotherapy used less across the 5 European countries compared with other regions. Treatment patterns were not heavily influenced by physician specialty, prior ADT duration, or Charlson Comorbidity Index score at inclusion.61The PROXIMA study, an international, real-world study of treatment patterns in patients with mCRPC previously treated with docetaxel in Asia, Europe, Latin America, and other countries from November 2011 to July 2015 found that, overall, hormone therapy was more frequently used as subsequent treatment than chemotherapy.62 In total, 45% of these institutions switched from systemic therapies to oral anti-cancer therapies due to the COVID-19 pandemic. This may, in part, explain the high level of NHT use seen in our study.It is important to consider that the data collection period overlapped with the COVID-19 pandemic, with most patients in this study initiating first-line mCRPC treatment in 2020. This may have impacted preferences for oral therapies that can be administered at home, rather than treatment requiring an in-person healthcare visit such as intravenous chemotherapy. A global survey of 129 healthcare professionals across 17 different countries, including the UK, Spain, and the US, found that all institutions in the study implemented some changes in the delivery of treatment.32-43 most patients did not receive an NHT in mCSPC. Results from a physician survey linked to patient chart reviews in the US suggest that this may be due to financial considerations as well as misperceptions of guidelines, tolerability, and efficacy, some of which may be overcome with further medical education.63 In addition to prior treatment exposure during mCSPC, approximately half of all patients who receive first-line mCRPC treatment go on to receive subsequent lines of treatment.59 It should also be noted that more treatment options will become available in the future, such as triple therapies, PARP inhibitors, PTEN loss therapies, immunotherapies, and lutetium PSMA. Thus, there will be an increasingly unmet need for further insight into the optimal treatment sequencing for patients with mCRPC.In our study, as in a number of claims-based analyses,Physician selection in the DSP is a potential bias as it is influenced by willingness to take part in the study and may not be representative of the overall population of physicians treating prostate cancer. A selection bias with regard to ethnicity may also result from the participating providers, which could have been overcome by targeting providers with a greater minority population. Another limitation results from the fact that patients with more frequent visits are more likely to be included in the sample than patients with less frequent visits to their physicians. It must also be recognized that the study included only consulting patients with mCRPC; survival bias likely skews the data toward patients at an earlier disease stage and may explain the low rate of visceral metastasis. In addition, only patients who received first-line treatment in mCRPC are included in the study. Our study may therefore not fully represent the overall population of patients with mCRPC. However, the systematic approach to recruitment intends to reduce selection bias.Although the overall sample size for this study was large, sample sizes per country and by patient demographic subgroups were small; future studies with larger sample sizes should investigate this further. Additionally, reimbursement for different medications varies widely by country and will therefore influence the treatment trends of each country studied. Reimbursement in European countries may vary by regions within countries; however, this level of analysis was not possible. Choice of mCSPC treatment may also reflect the historical lack of approved treatments. This reflects an inherent limitation of the constantly changing environment of real-world analyses. Further studies should explore time at-risk for mCSPC treatment and take historical treatment approvals into account, but our study does not have a sufficient sample size to conduct such an analysis.Our study uses descriptive analyses only and we are therefore unable to make conclusions based on comparisons between patient groups.While additional studies with larger sample sizes are needed, the findings of our real-world study suggest that physicians consider previous mCSPC treatments when making treatment decisions in mCRPC, and that their choice of first-line mCRPC treatment is impacted by NHTs moving earlier in the prostate cancer continuum. Insight into optimal treatment sequencing will become increasingly important with the anticipated increased use of NHT in the mCSPC setting and as new treatment options become available.The Oncologist online.Supplementary material is available at oyad046_suppl_Supplementary_FigureClick here for additional data file.oyad046_suppl_Supplementary_TablesClick here for additional data file.


N = 47 adolescents living with and without HIV in Cape Town, South Africa who speak isiXhosa at home. Reliability, convergent validity, and criterion validity were assessed, with T scores on the Achenbach System of Empirically Based Assessment Youth Self Report (YSR) form completed previously as reference standard. Our isiXhosa PHQ-9 exhibited satisfactory reliability, with Cronbach’s Depression is a debilitating illness, and stigma associated with it often prevents people from seeking support. Easy-to-administer and culturally- inclusive tools can allow for early screening for depressive symptoms in primary care clinics, especially in resource-limited settings. In this pre-registered pilot study (Stage 1 Report available at DOI: 10.3389/fpsyt.2022.840912), we produced an open-access isiXhosa-language version of the nine-item Patient Health Questionnaire (PHQ-9), a well-validated measure of depression incidence and severity, using a transcultural translation framework. We validated this isiXhosa PHQ-9 in a sample of  TheThe Xhosa people (‘amaXhosa’) comprise a diverse cultural group who speak variations of isiXhosa. The vast majority of amaXhosa live in the Eastern Cape and Western Cape provinces of South Africa . Over thThere is no word for ‘depression’ in isiXhosa, but that does not mean that this debilitating illness is not found among the amaXhosa. In fact, the prevalence of depression in this group, estimated at 6.9%, is significantly higher than global estimates for depression in the general population . SubstanThe nine-item Patient Health Questionnaire (PHQ-9) is a useful measure for depression incidence and severity . It has In this pilot study, we aimed to produce and validate one of the first open-access isiXhosa-language versions of the PHQ-9 depression scale. The protocol for this study was pre-registered in the Stage 1 Registered Report found at DOI: 10.3389/fpsyt.2022.840912. This isiXhosa PHQ-9 was produced using a transcultural translation framework and administered to a cohort of adolescents living with and without HIV in Cape Town, South Africa. Responses on the PHQ-9 were compared against those on the Achenbach System of Empirically Based Assessment (ASEBA) Youth Self Report (YSR) forms as a reference standard. Our primary hypothesis was that the isiXhosa-language PHQ-9 will exhibit satisfactory reliability, measured as internal consistency using Cronbach’s Participants for this study were recruited through the Adolescent Cognitive and Brain Imaging (GOLD) cohort at Stellenbosch University and Tygerberg Hospital in Cape Town, South Africa. The GOLD study, which draws on the cohort of participants in the landmark Children with HIV Early antiRetroviral therapy (CHER) trial, includes adolescents living with HIV who were initiated on antiretroviral therapy (ART) early in life . The CHEParticipants were included in this study if they were younger than 18 years old and spoke isiXhosa at home.A priori estimation of sample size in validation studies for psychometric tools is remarkably low  standards. The protocol for this study was approved by the Stellenbosch University Human Research Ethics Committee (N21/10/116_Substudy N19/10/135). Any participants who reported experiencing feelings of self-harm or suicide ideation or scored greater than 15 on the PHQ-9 were referred to a trained psychologist or social worker on staff for psychological support.any problems’ with ‘if you chose a number higher than 0’. The isiXhosa-language version of the PHQ-9 was created from this English version using a transcultural translation framework (see Procedure). Both the English-language and isiXhosa-language versions of the PHQ-9 are freely available in Supplemental materials.The English-language version of the PHQ-9 was designed with slight adaptations from the original version . The adaThe ASEBA YSR form  measuresThe study site for participant recruitment and data collection was the Family Centre for Research with Ubuntu (FAMCRU), Ward J8, Tygerberg Hospital, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University.The process of transcultural translation of psychometric tools involves steps to ensure that translated questionnaires remain accurate, relevant, and culturally acceptable . We adopTranslation from English into isiXhosa by two independent bilingual (English and isiXhosa) speakers;Review of isiXhosa translation by a panel of mental health experts, including research staff and clinical professionals, who speak both languages;Review of translation by a co-production panel involving individuals living with HIV and/or with a lifetime history of depression and who speak both languages; andBlinded back-translation from isiXhosa into English by two additional independent bilingual translators.The translated version was refined after each step to preserve the core meaning and purpose of each item and incorporate culturally specific idioms describing the affective components measured by the questionnaire where possible. Notably, these refinements were made to accommodate variations in language used by people in different geographical locations and to ensure that the translations were accessible to people who have not received a formal education. Modifications were reconciled in consultation with the translators and review panel involved in this process. The final isiXhosa-language version of the PHQ-9 is available in Supplemental materials.We also translated a demographic questionnaire, which included inclusive and diverse options for various gender identities and sexual orientations in both English and isiXhosa. This demographic questionnaire is available in Supplemental materials.Knowledge co-production, or participatory research methods, involves incorporating insights from individuals with lived experience of the conditions being studied. For this study, we recruited four isiXhosa-speaking individuals as a focus group to review and provide feedback on the isiXhosa translation of the PHQ-9 during the initial stages of this study. Two adults and two adolescents with lived experience of HIV and/or depressive symptoms were recruited through the FAMCRU clinic and the non-profit Inala Mental Health Foundation. These individuals were invited to review the isiXhosa PHQ-9 during Step 3 of the transcultural translation process and suggest edits to improve the accessibility, comprehensibility, and cultural sensitivity of the translation. Co-producers were reimbursed for their time.Participants were recruited through the GOLD study at the Family Centre for Research with Ubuntu (FAMCRU), Tygerberg Hospital. Adolescents living with or without HIV who met this study’s inclusion criteria were contacted by research staff to ascertain interest in participation in this study. A trained member of the research staff discussed the study procedures in person with the potential participant’s parent or legal guardian in their preferred language. Informed consent and assent forms were available in two versions (English and isiXhosa). Parents or legal guardians of the participants were asked to read and review the consent form. If participants agreed to take part in this study, written informed consent was received from parents or legal guardians in advance of the study procedures and verified by a doctor on staff. All participants were also required to assent to the study procedures. Participants were reimbursed for their travel costs to visit the clinic for the study in line with Stellenbosch University policies.Participants were provided a private space for psychometric testing. A member of the research staff briefed each participant on the procedures involved in the study and receive informed assent. The research staff confirmed that the participant would prefer to respond to questionnaires in isiXhosa and offered them a choice between filling out the questionnaire themselves in writing or having the research staff ask them the questions verbally (for participants who may not be able to write or have a preference for spoken isiXhosa over written isiXhosa). If participants chose to complete the psychometric testing in writing, they were asked to fill out a short demographic questionnaire and the translated version of the PHQ-9 in writing (paper and pencil). If participants chose to complete the questionnaire verbally, the member of the research staff read each item on the questionnaire exactly as written in a neutral manner and wrote down the participant’s response, without judgement or comment. In either case, the research staff member was available to the participant for any clarifications to ensure participants understood what each question was asking. Once participants completed the demographic questionnaire and the PHQ-9, the research team member verified that all nine items of the PHQ-9 were completed. The research team member calculated the total score on the PHQ-9 as the sum of the scores from individual items and input responses into a secure electronic database (Project RedCap), which included built-in quality control checks. Data were handled in accordance with the Protection of Personal Information Act (South Africa) and the UK General Data Protection Regulation (GDPR) Act.n and %) for categorical variables, and medians and interquartile ranges (IQRs) for continuous variables.All statistical analyses were performed using R version 4.2.1. Participant demographic characteristics were summarised using proportions  method to adjust for multiple comparisons.To determine the reliability of the isiXhosa PHQ-9, we calculated Cronbach’s Certain deviations from the protocol described in the Stage 1 Registered Report are noted. First, the Stage 1 Registered Report indicated that only adolescents living with HIV would be recruited. However, given that the validity of the PHQ-9 is not specific to this population and to ensure the maximum possible power for our analyses, we included both adolescents living with and without HIV in this study. Second, the Stage 1 Registered Report indicated that the PHQ-9 and YSR scores would be separated by no more than 3 months, but this was not possible due to practical constraints in participant scheduling. We, therefore, report the median absolute time difference between the YSR and PHQ-9 administration. In all cases, the most recent YSR scores available for each participant were included for analysis, and the YSR and PHQ-9 were administered as closely as possible, as was indicated in the registered protocol. To ensure that these deviations from the registered protocol did not substantially impact our findings, we conducted sensitivity analyses, which are described below.In addition to pre-registered analyses described above, we carried out descriptive analyses of group differences, as our sample included both participants with and without HIV. Group differences in demographic characteristics were assessed using Pearson’s chi-square test or Fisher’s exact test for categorical variables, and Wilcoxon rank sum test for continuous variables. Group differences were assessed by HIV status, comparing participants with HIV and participants without HIV, and depressive symptom status, comparing participants with total PHQ-9 score We also investigated the construct validity and factor structure of our isiXhosa-language PHQ-9. We conducted a principal component analysis  to calculate eigenvalues and factor loadings for each item on the questionnaire. A scree plot was produced using variance explained for each component to confirm number of factors. Tucker’s coefficient of factor congruence was calculated to assess the congruence between factor loadings in our sample with other reported PHQ-9 validation studies. To ascertain whether the variability in factor loadings for each item in our translation may be attributed to the small sample size in our pilot study, a bootstrap analysis was run (R function ‘boot’) with 1000 sets of bootstrapped factor loadings based on our observed factor loadings. Using the bootstrap output, bias corrected accelerated 95% confidence intervals  and most identified as heterosexual n = 35, 74.5%) were all receiving ART, and 91.4% were virally-suppressed , although as the utility of the PHQ-9 as a screening tool for depressive symptoms is not limited to people living with HIV, we did include participants without HIV  in this study. Participants did not differ on demographic characteristics when stratified by HIV status, except participants with HIV were slightly older, and a greater proportion of participants without HIV were boys.Demographic characteristics by subgroups of HIV status and depressive symptoms are reported in n = 16 (34%) participants met the criterion for ‘some depressive symptoms’ . Participants did not differ on demographic characteristics when stratified by depressive symptoms, except participants with some depressive symptoms were more likely to report having used recreational drugs in the past 6 months.Median (interquartile range (IQR)) total score on the PHQ-9 was 3 , with a range of 0–17. Of the full sample, Median (IQR) absolute time difference between administration of the PHQ-9 and YSR was 92  days.Cronbach’s .730 see . Mean  validation study recently carried out, which reported PHQ-9 data pooled from participants in seven countries  and administered in five languages  differed significantly between our data set and the larger pooled validation data set, t(29) = –7.11, M = 0.43, SD = 0.54) was lower than that in the sample of Bianchi et al. .Item-level mean scores for our isiXhosa PHQ-9 were comparable to those from a large . The correlation between total PHQ-9 score and T score on the Anxious/Depressed component of the YSR was not significant (Spearman’s p = 0.419). Thus, the isiXhosa PHQ-9 demonstrated acceptable convergent validity with the Withdrawn/Depressed component of the YSR, but not with the Anxious/Depressed component.There was a moderate significant association between total PHQ-9 score and T score on the Withdrawn/Depressed component of the YSR  and iten = 35) only. Sensitivity analyses of reliability showed that the Cronbach’s To assess whether the inclusion of participants without HIV in this study may have influenced our findings, we conducted sensitivity analyses for the subset of participants with HIV (p = 0.002), but no significant correlation between total PHQ-9 score and anxious/depressed T score (Spearman’s p = 0.417). Finally, we assessed criterion validity in only the subset of participants for whom the PHQ-9 and YSR were administered less than 100 days apart (n = 25). Of this subset, n = 6 participants met criteria for clinical or borderline depression on the YSR. The ROC curve and diagnostic performance characteristics for this subset are available in Supplemental materials. AUC (95% CIs) was 0.79 , indicating satisfactory discrimination. A threshold of PHQ-9 score To assess whether the greater time difference between PHQ-9 and YSR administration may have influenced our findings, we conducted further sensitivity analyses. For convergent validity, we calculated partial Spearman’s correlation coefficients adjusted for absolute time difference between the two assessments. Findings remained consistent, with a moderate significant association between total PHQ-9 score and withdrawn/depressed T score , 0.78 (h Africa ), and 0.h Africa ) for theh Africa  and Mozah Africa ). OveralItem-level mean scores in our study were comparable with the large, global sample reported by A key limitation of this study is the small sample size and low prevalence of depressive symptoms. Despite the increased overall power afforded to the study by our larger-than-planned sample size, the proportion of participants who were classified as ‘clinically depressed’ or ‘borderline depressed’ on the YSR was extremely small. As a result, assessments of criterion validity were underpowered. Larger validation studies in future are necessary to assess criterion validity of this isiXhosa PHQ-9 with sufficient power. Another potential limitation is that the diagnostic performance of our isiXhosa PHQ-9 was compared against the YSR as a reference standard, rather than a clinical diagnostic interview, and that the PHQ-9 and YSR were not administered on the same day. The YSR has been shown to predict a ‘true’ diagnosis of depression (i.e. determined using an interview by a psychiatrist) with acceptable sensitivity and specificity . Neverthhttp://depressionscreening100.com/phq/.) Moreover, measurement of depressive symptoms on a continuous scale, rather than categorical incidence of MDD, can be useful in identifying symptom clusters, tracking subtle changes in symptom severity, or assessing efficacy of antidepressant interventions beyond a strict diagnostic binary. For these reasons, there is intrinsic value in the assessment of the utility of the isiXhosa PHQ-9 as a screening tool for a continuous spectrum of depressive symptoms, and in comparison with other screening tools, rather than an over-emphasis on comparisons with clinical diagnostic tools.However, it must be noted that the PHQ-9 itself is a screening tool, which may support triage for people experiencing depressive symptoms, before a comprehensive diagnostic evaluation by a clinician is carried out. Although defining a cut-off on the PHQ-9 can enable putative diagnosis of MDD, this questionnaire is not in fact sufficient for diagnosis. More broadly, measurement of depressive symptoms – including using screening tools such as the PHQ-9 – suffers from substantial methodological and theoretical challenges, which impair our ability to accurately detect depression.  DependinAt the time of registration of our Stage 1 Registered Report, there was no openly available isiXhosa translation of the PHQ-9. Since then, another research group has independently produced a similar isiXhosa-language PHQ-9, which merits discussion. isiXhosa is a primarily oral language, and many amaXhosa (particularly young people) are more comfortable with spoken isiXhosa than written isiXhosa. In keeping with this, many of our adolescent participants requested that the isiXhosa PHQ-9 be read aloud to them. Assessments of emotional or behavioural states may be most accurate when conducted in participants’ home language and in a format in which they are most comfortable. We have, therefore, identified the need to standardise and optimise this process. One solution is to produce an audio-recorded version of the isiXhosa PHQ-9, which may be administered digitally (in an app format) with recordings playing alongside the text of the questions. In future, we hope to produce this app-based version of the isiXhosa PHQ-9, which may allow access to this screening tool for participants who can speak (but not read) isiXhosa, as well as reducing staff burden and minimising inter-interviewer variability.In this pilot study, we have demonstrated that our isiXhosa translation of the PHQ-9 exhibits satisfactory psychometric properties. Larger, independent validation studies are necessary to further characterise the diagnostic performance of this isiXhosa PHQ-9 as our analysis of criterion validity was under-powered, although the study by Click here for additional data file.Supplemental material, sj-csv-5-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-csv-6-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-csv-7-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-csv-8-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-csv-9-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-docx-1-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-docx-2-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-docx-3-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-docx-4-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-tiff-10-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-tiff-11-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience AdvancesClick here for additional data file.Supplemental material, sj-tiff-12-bna-10.1177_23982128231194452 for isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2] by Arish Mudra Rakshasa-Loots, Thandi Hamana, Busiswa Fanqa, Filicity Lindani, Kaylee van Wyhe, Sharon Kruger and Barbara Laughton in Brain and Neuroscience Advances


Prophylaxis therapy for children with moderate and severe hemophilia A (HA) is the optimal treatment regimen. The real-world treatment regimens, patient-reported outcomes, and health-related quality of life (HRQoL) in children with moderate and severe HA in China are less known.This study aimed to describe real-world treatment regimens and evaluate the association of treatment regimens with comprehensive patient-reported outcomes including bleeds, chronic pain, target joints, disability, and HRQoL in children under 18 years old with HA in China.Real-world data of a nationwide online cross-sectional survey in 2021 and patients’ coagulation factor utilization data from self-management records from 2020 to 2021 were merged. 373 eligible children were included and categorized by treatment regimens according to the Chinese guideline: on-demand, short-term prophylaxis, and long-term prophylaxis treatment.Currently, in China, 4.8% of children with HA are receiving full-dose long-term prophylaxis treatment. Prophylaxis treatment was a significant positive predictor of better patient-reported outcomes and HRQoL. For children with prophylaxis treatment, there were significantly fewer annual bleeds (p < 0.001), lower frequency of chronic pain(p < 0.001), and higher health utility scores(p < 0.01) and EQ-VAS scores(p < 0.05) than children with on-demand treatment.Accessible long-term prophylaxis treatment should be promoted for children with moderate and severe HA in China and regular monitoring of their outcomes and HRQoL should be carried out. Hemophilia is a rare, inherited bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII) (in hemophilia A) or factor IX (in hemophilia B) . HemophiContinuous prophylaxis treatment is broadly recommended as the optimal regimen and the standard care for children with moderate and severe HA , 4. PropIn China, it was estimated more than 65,000 patients live with hemophilia . Due to Although some local studies explored the association of prophylaxis treatment with patient-reported outcomes and HRQoL among adults with hemophilia in China –29, few This study aimed to fill the gap in the literature using real-world data to compare the association of different treatment regimens with patient-reported outcomes and HRQoL of children with HA living in China.In this study, patients were included by the following inclusion criteria: (1) Chinese patients who were diagnosed with HA; (2) patients with moderate HA (FVIII = 0.01 to ≤ 0.05 IU/mL) and severe HA (FVIII < 0.01 IU/mL);(3) patients without FVIII inhibitors; (4) patients no more than 18-years-old; and (5) patients and their caregivers provided informed consent.To identify eligible patients across the country and conduct an investigation, we collaborated with the Hemophilia Home, which is the biggest hemophilia patient organization in China, having over ten thousand registered patients. Target patients were sampled from the registered patients of this organization.HA children’s real-world data were collected from two parts and merged with each other. Firstly, patients’ demographic characteristics, patient-reported outcomes, and HRQoL were collected in July 2021 through a nationwide online cross-sectional survey embedded in the Hemophilia Home’s Apps. An invitation letter introducing the purpose and procedure of this survey was sent out to all registers of Hemophilia Home. The patients and their caregivers who agreed with the term and gave full informed consent were invited to fill out the questionnaire via Apps. Parents of children who are less than 8 years old or over 8 years old but unable to complete the questionnaire reported the related information for their children. Individual data on disease history, and patient-reported outcomes including bleedings, pains, target joints, and disability in the last 12 months were collected. EQ-5D-5 L scale was employed to measure the health-related quality of life among patients.Secondly, patients’ use of FVIII was collected from the patient self-management database from the Hemophilia Home’s Apps for the same group of the participant in the national survey. Hemophilia Home encouraged registered patients to upload accurate, real-time information on the use of FVIII by scanning the QR code on the outer packing when infusing. After identifying the survey responders, their records of FVIII utilization from July 2020 to June 2021 were extracted from the patient self-management database.The Institutional Review Board Ethics Committee of Fudan University approved the study protocols (Ref no.: IRB#2022-02-0951).-1 of body weight and frequency was two times per week lasting for at least a year. After analyzing annual factor consumption and body weight for each patient, three treatment regimens were defined and classified by this standard from the guideline:Treatment regimens were analyzed based on the records of FVIII utilization and patients’ body weights from the database. According to Chinese guidelines on the treatment of hemophilia (version 2020) published by the Chinese Society of Hematology Thrombus and Hemostasis Group and Chinese Hemophilia Cooperative Group , the staOn-demand treatment: patients receive on-demand treatment only after the occurrence of bleeding.Short-term prophylaxis treatment: patients receive prophylaxis treatment not up to the standard from the Chinese guideline. They might lack dose according to their body weights or not reach the required frequency (two times per week).Long-term prophylaxis treatment: patients receiving prophylaxis treatment up to the standard. They must receive the standard dose according to their body weights and also takeinfusions two times per week.Consisting with the existing clinical definitions and standards in Chinese guidelines on the treatment of hemophilia (version 2020) , the relAnnual bleeds were defined as the total number of bleeds for each patient in a year. The results were derived from the patient’s self-reported bleeding times, which were collected in the survey using a single question “How many bleeds have you had in the past year?”Chronic pain was defined as pain related to hemophilia from a persistent cause. It was asked with the question “During the past 12 months, have you experienced chronic pain due to hemophilia ?”. The answers were classified into 5 levels according to the frequency of occurrence: never (0% of the time), occasionally (less than 25% of the time), sometimes (25-50% of the time), frequently (50-75% of the time), and always (more than 75% of the time) and the ordinal variable was used for analysis.Target joints were defined as the total number of swollen joints with limited movement and chronic synovitis. The question was “How many target joints have you had told by the doctors currently?”Disability was defined as whether a patient was judged as statutory disabled. It was assessed by the question “Wereyou judged as the statutory disabled with a legal certificate or not?” and the dichotomous variable was generated. The legal certificate is accessible to make evaluations for patients and is broadly accepted as the standard of disability in China.HRQoL of patients was measured by the EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score and visual analogue scale (EQ-VAS). Firstly, a patient’s health is measured in five dimensions including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and every dimension is divided into five levels, ranging from 1 to 5 as the score. Using the value set for the Chinese population , the scoDescriptive statistics were used to describe the patients’ characteristics, treatment regimens, patient-reported outcomes, and HRQoL. The mean and standard deviation for continuous variables and numbers and proportions for categorical variables are reported. To evaluate the differential association of treatment regimens with patient-reported outcomes or HRQoL among treatment regimens, the multivariate linear regression model was conducted for annual bleeds, target joints, EQ-5D-5 L utility scores, and EQ-VAS scores, and the logistic regression model for disability and the ordinal logistic regression for chronic pain were employed. Other related factors were controlled including age group, body mass index (BMI), health insurance, regional location, hemophilia severity, and having infectious blood disease.The statistically significant level was 0.05. The Statistics Data Analysis (STATA) software, version 15.1  was used for all the analysis.Real-world data of 373 children with HA without inhibitors from 29 provinces were collected. The characteristics of these patients are reported in Table According to the classification from the Chinese guideline and patients’ real-world data on FVIII use, only 4.8% of HA children received long-term prophylaxis treatment, 73.2% received short-term prophylaxis treatment, and 22.0% received on-demand treatment. HA children, who were not overweight, with severe hemophilia, without infectious blood disease, and lived in the Eastern regions were more likely to receive short-term or long-term prophylaxis treatment.Patient-reported outcomes and HRQoL of children with different regimens were shown in Table The results of the multivariate regression models concerning the association of treatment regimens effect with patient-reported outcomes and HRQoL were presented in Table Children with prophylaxis treatment had fewer target joints and less probability of disability. However, neither of these differences among treatment regimens was statistically significant. The mean target joints for children with long-term prophylaxis treatment was 0.3, while children with other treatments had 0.7 target joints on average. No children with long-term prophylaxis treatment were disabled, while 8.5% of children with on-demand treatment and 4.8% of children with short-term prophylaxis treatment were disabled.Treatment regimens were significantly and positively related to health utility scores and EQ-VAS scores. Patients receiving short-term and long-term prophylaxis treatment had higher scores of health utility and higher scores of EQ-VAS than patients receiving on-demand treatment. For patients with on-demand treatment, the mean health utility scores were 0.804, and EQ-VAS scores were 71.96. For patients with short-term prophylaxis treatment, the health utility scores  and EQ-VAS scores  were higher. For patients with long-term prophylaxis treatment, the mean health utility scores  and EQ-VAS scores  were highest than patients with the other two treatment regimens. Either difference in health utility scores and EQ-VAS scores among treatment groups was statistically significant (p < 0.01 and p < 0.05).To show more comprehensive and detailed results, the multivariate regression models of treatment regimens effect for two subgroups of hemophilia severity were displayed in Table This study described real-world treatment regimens of children with moderate and severe HA in China and comprehensively compared their patient-reported outcomes and health-related quality of life. It suggested that prophylaxis treatment was a significant positive predictor of better patient-reported outcomes and HRQoL. There were significantly fewer annual bleeds, lower frequency of chronic pain, and higher health utility scores and EQ-VAS scores for children with prophylaxis treatment than for children with on-demand treatment. Children with long-term prophylaxis treatment had the best health outcomes.This study revealed that only 4.8% of children with HA were receiving full-dose prophylaxis treatment currently in China, which is far below that proportion in developed countries. Among children receiving any kind of prophylaxis treatment, over 90% haven’t reached the standard of the full dose of long-term prophylaxis treatment from the Chinese guideline. It was reported that nearly 94% of patients in the United Kingdom , 77% of Consistent with former studies, this study suggested that prophylaxis therapy decreases the frequency of hemorrhages, which is beneficial to prevent the progression of hemophilic complications , 14, 17.Like other studies, our results also suggested that patients who receive prophylaxis treatment have a significantly higher quality of life , 19, 20.This study has some strengths. As we know, it is the first study to comprehensively evaluate the influence of treatment regimens among children with moderate and severe HA in China by using four measures to assess the patient-reported outcomes and two measures to reflect the physical and psychosocial health status . Real-woIn conclusion, this study provides new evidence in China that children with HA, who received prophylaxis treatment have fewer annual bleeds, lower frequency of chronic pain, and higher health utility scores and EQ-VAS scores than on-demand treatment. Accessible long-term prophylaxis treatment with abundant infusion of FVIII should be evenly promoted as the optimal treatment regimen for children with moderate and severe HA in China and regular monitoring of its outcomes should be carried out in the future.


P = 0.007, I2 = 45%). Regarding immunological outcomes, the risk of SARS-CoV-2 infection during pregnancy or postpartum was significantly reduced in 6820 vaccinated pregnant women compared to 17,010 unvaccinated pregnant women , as evident from qualitative assessment indicating significantly higher postpartum antibody titers compared to that observed in both unvaccinated mothers and mothers who have recently recovered from a SARS-CoV-2 infection. Our analysis represents high quality evidence showing that COVID-19 vaccination effectively raises antibody titers against SARS-CoV-2. This may confer protection against infection during pregnancy and the postpartum period. In addition to being protective against SARS-CoV-2, the vaccine was associated with decreased odds of preterm delivery. Furthermore, COVID-19 vaccination may also be associated with higher odds of cesarean section.Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with increased pregnancy complications. Despite effective vaccination strategies for the general population, the evidence on the safety and efficacy of Coronavirus disease 2019 (COVID-19) vaccinations in pregnancy is limited due to a lack of well-powered studies. The present study compares the maternal, neonatal, and immunological outcomes between vaccinated pregnant and unvaccinated pregnant women using a systematic review and meta-analysis approach. We included 37 studies with a total of 141,107 pregnant women (36.8% vaccinated) spread across all outcomes. Our evidence indicates a higher rate of cesarean section in the 1898 vaccinated pregnant women compared to the 6180 women who did not receive vaccination ,  COVID-19 vaccines have also been shown to elicit strong protective responses in highly susceptible older adults and individuals with weak immune systems. A recent study has also found that pregnant women are more susceptible to presenting a more severe form of SARS-CoV-2 pneumonia than non-pregnant women and have higher rates of SARS-CoV-2-induced intensive care unit (ICU) admission, oxygen supplementations, need for mechanical ventilation, and death3. The virus can also affect neonatal outcomes, affecting up to 27% of infected mothers, who may suffer premature rupture of membranes, decreased fetal perfusion, and preterm births4. Other studies have shown that the incidence of preterm birth was tripled in symptomatic infected women compared to asymptomatic ones5. Also, blood hypercoagulability during SARS-CoV-2 infection increases the risk of thromboembolic events in pregnant women6. Studies have also reported an increased incidence of preeclampsia-like symptoms in infected mothers, such as hypertension, immune dysfunction, and thrombocytopenia without preeclampsia7. These complications and the severity of SARS-CoV-2 infection in pregnancy are likely due to the physiological changes in pregnant women, including increased cardiovascular requirements, decreased lung capacity, and immunological changes that are otherwise generally accepted to approximate a mildly immunocompromised state8.There is a growing body of evidence that vaccination against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to considerably reduce the burden of Coronavirus disease 2019 (COVID-19)10. However, the efficacy and safety of COVID-19 vaccination in pregnancy are unclear. Most COVID-19 vaccine trials failed to include pregnant women due to ethical concerns and the generalizability of the resulting data12. Animal data regarding the AstraZeneca vaccine’s usage in pregnancy has been reassuring, without any complications seen in comparable doses in mice13. In addition, data received from unintentionally vaccinated pregnant women from the COVID-19 immunization registry has thus far shown very few complications related to vaccine safety14. However, the lack of clinical trials still may make some women hesitant to receive COVID-19 vaccines, and this is an area where additional data is greatly needed15. Therefore, we performed this systematic review and meta-analysis to compare the maternal and neonatal outcomes between vaccinated pregnant and unvaccinated pregnant women, as well as to determine the antibody titers patterns of COVID-19 antibodies in both maternal and umbilical cord samples, and to determine the efficacy of vaccinations against COVID-19 administered during pregnancy to prevent COVID-19 infection.Vaccination, in general, is usually safe during pregnancy, except for live attenuated vaccines51. Characteristics of included studies are shown in Supplementary Table Our database search resulted in 2036 records; 585 studies were removed as duplicates, and 1451 records remained for the title and abstract screening. Figure 16, and two provided sample size justification28. Supplementary Table The overall mean result of the quality assessment was 8.75 (SD = 1.06), with none of the studies scoring <7 (low-bias) on a scale of 1-14. Notably, only one study reported data concerning blinding the outcome assessmentThe results of the meta-analysis of the association of respective maternal, neonatal and immunological outcomes with vaccination status in pregnant women are summarized in Supplementary Table P = 0.007, I2 = 45%, Phet = 0.14; based on 4 studies)48   46  Fig. 18,20,23,)46 Fig. .Fig. 4FoDue to the limited combinability of various immunological outcomes, including antibody levels and transfer ratios, we qualitatively synthesize the available evidence on the influence of vaccination on these outcomes.51. A complete summary of the study characteristics along with their findings are further shown in Supplementary Table 44. Gray et al.26. found that the highest increase in IgG levels occurred ~2–6 weeks after the second vaccination inoculation. On the other hand, while IgM and IgA were detected after the first dose, a significant increase in their levels was observed only after the second dose26. Notably, IgA levels were higher in women vaccinated with the mRNA-1273 vaccine than those vaccinated with the BNT162b2 vaccine26. Furthermore, anti-spike protein antibodies seemed to be induced more rapidly than anti-RBD antibodies26.Sixteen studies assessed antibody titers in vaccinated maternal serum49. For instance, Shanes et al. noted that IgG and IgM antibody levels were significantly higher in 52 vaccinated pregnant women than those observed in 116 unvaccinated pregnant women44. Several other studies reported higher antibody levels in vaccinated pregnant women than the unvaccinated pregnant women, who were known to have recovered from a recent SARS-CoV-2 infection38. Interestingly, stratification of IgG subtypes by Beharier et al. resulted in a more accurate assessment of immune response in vaccinated pregnant women. The authors observed higher levels of anti-RBD IgG and anti-spike S1 IgG and lower levels of anti-spike S2 IgG and anti-nucleocapsid IgG in vaccinated pregnant women16 simultaneously. These findings contrast with that reported by Yang et al., who failed to observe any difference in anti-spike IgG levels in vaccinated pregnant women compared to SARS-CoV-2 infected non-pregnant women, which could be due to a lack of information on the anti-spike subtype of IgG49. Some studies also investigated the influence of vaccination on antibody levels in pregnant women than that observed in non-pregnant women. We observed mixed findings; while some observed lower levels in pregnant women, others failed to detect any difference26.A few studies compared antibody levels in vaccinated pregnant women to unvaccinated pregnant women, showing a favorable response to vaccination49. Concerning the timing of vaccination, most studies found a positive correlation between levels of antibodies and gestational age of vaccination49. Yang et al. further observed a subsequent decline in anti-spike IgG after the 34th week of gestation49. By contrast, Gray et al. observed no significant correlation between the antibody levels and the trimester during which the vaccination was administered26. Maternal IgG levels at delivery were further dependent on the time passed since the first or second dose of the vaccine. For instance, Prahl et al. found no significant correlation between maternal IgG levels and time since the first dose administration, attributed to some participants receiving the first dose vaccine only 30 days prior to delivery40. Some studies also showed that the anti-RBD IgG at delivery correlated negatively with the time since the reception of the first41 or second vaccine38. Another study investigating pregnant women vaccinated with Johnson & Johnson vaccine did not show any difference in anti-spike protein IgG levels correlating with the timing of vaccination49.Several factors have been investigated that could play an essential role in determining efficacy of vaccination in pregnant women, including the number of vaccine doses administered and gestational age at the last vaccination. The administration of an additional or “booster” dose universally increases anti-spike IgG antibodies in fully vaccinated women51. Nearly all studies reported high levels of IgG in cord samples of vaccinated women irrespective of subtype (anti-RBD or anti-spike) assessed51. None of the studies detected IgM antibodies in the umbilical cord41. The IgG levels were lower in pregnant women who delivered after being administered the first dose of the vaccine than those who received both doses39. In a follow-up study, the dosage effect was further evident with IgG detection in only 9 of the 11 infants whose mothers received two doses prior to delivery (weeks of life range mean = 8.3). One of these infants continued to be positive for IgG at 12 weeks of age40.Sixteen studies assessed antibody titers in the umbilical cord blood of vaccinated mothers at the time of delivery30. Similar findings were observed when anti-RBD or anti-spike IgG levels in umbilical cord blood of neonates born to vaccinated women compared to those observed in unvaccinated SARS-CoV-2 infected pregnant women with a known recovery from the SARS-CoV-2 infection38. Another study failed to observe any difference in the distribution of anti-RBD or anti-S1 IgG between fully-vaccinated women compared to women with a prior SARS-CoV-2 infection16. Interestingly, the study also reported lower anti-nucleocapsid or anti-S1 IgG levels in fully vaccinated women16.Several reports have shown significantly higher levels of different antibody subtypes compared to unvaccinated pregnant women with no known history of SARS-CoV-2 infection49. Concerning the timing of vaccination, most studies found a positive correlation between levels of antibodies (anti-spike or anti-RBD IgG) and gestational age of vaccination49. The correlation was specifically stronger after the second dose of vaccination41. Yang et al. further observed that higher levels of antibodies were limited to the 32nd week of gestation, when their levels started declining49. The time since the first of the two administered doses of the vaccine also shows a positive correlation with anti-RBD and anti-spike IgG levels in umbilical cord blood51. However, the results showed considerable variation when the time since the second dose of the vaccine is considered. While Gray et al. observed a positive correlation between anti-spike IgG and time since administering the second dose of vaccine, Nir et al. failed to observe any correlation38. Another study reported a negative correlation between anti-RBD IgG levels and time since the administration of the second dose31.Similar to the effect of additional dose administration on anti-spike IgG levels in sera of pregnant women with no history of SARS-CoV-2 infection, studies have reported significantly increased induction of anti-spike IgG in umbilical cord blood of vaccinated pregnant women compared to fully vaccinated women with negative history of SARS-CoV-2 infection. However, this difference is not retained when boosted vaccinated non-infected women were compared to women with a known history of SARS-CoV-2 infection and recovery51. Results varied widely between studies. While Zdanowski et al. reported a notably high transplacental antibody transfer ratio (mean ± SD = 1.28 ± 0.798)51, it was observed to be low for anti-RBD IgG by Nir et al. (median = 0.77)38 and Rottenstreich et al. 42. Another study reported a significantly lower transfer ratio for anti-S1 IgG, anti-S2 IgG, anti-RBD IgG in vaccinated pregnant women compared to previously infected women16. Generally, the transplacental ratio correlated positively with the time elapsed from vaccine dose to delivery51. Zdanowski et al. further observed a significantly higher transplacental ratio in early third-trimester vaccination than in late third-trimester vaccination41.Nine studies reported the transplacental antibody ratio 53. It is notable however, when taking into account the small number of COVID-19 cases in the unvaccinated population, that some of the tendency to deliver early may be iatrogenic, especially earlier in the pandemic. The odds of cesarean delivery are also significantly higher in the vaccinated group, while no clear explanation exists for this phenomenon. Other than these results, we found no significant differences between the vaccinated and unvaccinated groups concerning maternal and neonatal outcomes. Unfortunately, secondary to varying definitions of “fully vaccinated” in the different included studies, we could not carry out stratified analysis for each of these definitions due to lack of power to perform such an analysis. It should be noted that we adopted the random effects model to help account for these heterogeneous findings.Overall, our systematic review and meta-analysis show that the administration of the COVID-19 vaccine to pregnant women is safe and effective. The odds of SARS-CoV-2 infection are significantly lower in the vaccinated group, compared to unvaccinated women. This evidence supports guidelines from major groups recommending universal vaccination during pregnancy. Our finding of decreased odds of preterm delivery in vaccinated women is not surprising as several studies have demonstrated the connection between SARS-CoV-2 infection in pregnancy and preterm delivery55. In all cases, vaccinated pregnant women showed higher titers of anti-RBD antibodies when compared to previously infected unvaccinated women56. On the other hand, unvaccinated SARS-CoV-2 infected pregnant women showed lower antibodies titers when compared to vaccinated pregnant, lactating, and non-pregnant women22. Meanwhile, the vaccinated women had significantly higher anti-RBD IgG and anti-S1 IgG levels than infected women, while significantly higher levels of an anti-S2 segment of spike protein IgG and anti-Nucleocapsid IgG antibodies in infected women compared to vaccinated women16. The antibody response was affected by additional or “booster” dose administration, the trimester time of vaccine administration, and the time passed from the first or second vaccine dose55. Administration of the second vaccine dose to the women achieved higher titers of anti-RBD and anti-spike protein IgG in umbilical cord samples of the neonates compared to those born to women who took the first dose only54. Non-infected unvaccinated women had negative antibody samples, while vaccinated pregnant women showed high antibody titers57. Neonates born to vaccinated women showed higher anti-RBD and anti-spike protein IgG titers than those born to SARS-CoV-2 infected unvaccinated women22. As for transplacental antibody transfer, SARS-CoV-2 infected women had a higher IgG transfer ratio for the anti-S1 segment of spike protein, the anti-S2 segment of spike protein, and anti-RBD than the vaccinated, negative anti-Nucleocapsid group; however, no significant difference was found between positive anti-Nucleocapsid vaccinated women and the other two groups16.Concerning maternal humoral immunity, although factors related to combinability limited the possibility of a quantitative synthesis, we can report several findings. First, all pregnant women who received any vaccination showed high anti-RBD or anti-spike protein antibody levels. There was no evidence of ineffective vaccination. In all cases, the level of IgG was higher than IgM58. On the other hand, only 1 of 12 infants (8%) born to infected mothers had detectable antibodies at 6 months. However, IgM antibodies have not been detected in cord blood samples indicating that they do not cross the placenta, which could be attributed to their large macromolecular structure59. Antibodies in the milk from lactating women who had received COVID-19 vaccine have been shown to neutralize spike and several variants of concern60. The immune response to maternal vaccination was also reflected in detection of antibodies in 1/3rd of breastfed infant stool60.Several studies have highlighted that vaccinated or infected pregnant women can transfer antibodies against SARS-CoV-2 to the fetus. The vaccination specifically generates anti-spike IgG antibodies which have been detected in the umbilical cord, Furthermore, the antibodies continue to be detected in infants after birth. A recent study of 28 infants of vaccinated mothers reported significantly higher titers at 6 months in 16 infants (57%)61. On the contrary, we found that the vaccinated group had significantly lower odds of preterm delivery and higher odds of cesarean section than the non-infected unvaccinated group. Other reviews and meta-analyses demonstrated the efficacy and safety of the COVID-19 vaccine for pregnant women and found that the administration of the vaccine to pregnant women was safe and effective. Many also recommended administering an additional or “booster” dose, which may induce a higher antibody response64. These results agreed with our study results, but our analysis included the largest number of studies. Ma et al. included only six studies64, Fu et al. included 23 studies63, Pratama et al. included 12 studies62, while our study included 37 studies. Moreover, our analysis illustrated the factors affecting antibody response for mothers and their fetuses in more detail.Similar to our study results, Pratma et al., in their meta-analysis and systematic review, found that the administration of mRNA vaccine to pregnant women effectively reduced the incidence of further SARS-CoV-2 infections and provided antibody response to the pregnant women and their fetuses which was increased by administration of a second vaccine dose. Additionally, they found the vaccine-induced higher antibody titers compared to that produced by SARS-CoV-2 infection without vaccination. They also found that the vaccine had no significant effect on maternal, delivery, and neonatal outcomes65. This 2022 retrospective cohort study compared pregnant women of different vaccination statuses during pregnancy. They found, similar to our results, a slightly higher rate of gestational diabetes among those women vaccinated against COVID-19. There was also a slightly increased rate of delivery of Cesarean deliveries amongst the triple vaccinated compared to the non-vaccinated, also similar to the present study. It will be interesting to see if these small differences exist in future studies and what causes they could be attributed to.Also in agreement with our findings are some of the results of the recently published Dick et al.66. Tomasz et al. found that the vaccine’s acceptance rate among pregnant women ranges between 29.7% and 77.4%. This range depends on many factors, the most important of which are the awareness of the infection, the safety of the vaccine, and the way to provide information about the vaccine and its safety67. It should be noted, however, that because of the absence of follow-up data for both mother and the infant, long term safety and efficacy of COVID-19 vaccines cannot be judged using only the present study. Developing resistance among SARS-COV-2 variants represents another problem that should be taken into consideration69. Moreover, there are mutations in some variants that affect the virus’s transmissibility and severity. These mutations also affect the COVID-19 treatment efficacy70. This problem could create a need for additional vaccine formulations to better protect populations71. We consider the COVID-19 pandemic to be a rapidly evolving situation with a constant need of updating vaccines to target newer variants of concern. Although the findings from the present study may not be directly applicable to the current pandemic, they will likely help in designing better vaccines in future.There are some obstacles to managing the SARS-CoV-2 pandemic and achieving herd immunity. Acceptance of COVID-19 vaccination is an important one of these issues. Wake et al. found that acceptance of the vaccine was very low in AfricaThe main strength of our comprehensive meta-analyses is the incorporation of the latest studies resulting in the largest sample size reported to date for multiple study outcomes. However, the inclusion of observational studies which were often unmatched continues to be the main limitation in judging the evidence, especially in light of the fact that the included observational trials largely gave only immunological, not clinical outcomes. Furthermore, considerable heterogeneity in vaccine type, dosing and schedule, and measurement of different antibody subtypes, often made the comparison and pooling of various outcomes highly challenging. In addition, there is always the possibility that IgG levels may be under-estimated in the serum of the study participation. If future studies were to measure the SARS-CoV-2 antibody in the saliva instead, this may provide a better measurement of the degree of protective immunity against COVID-19. Another limitation included the fact that our study fails to account for the role of T-cells and innate immunity. It is possible that a large majority of uninfected adults may already have pre-existing antibodies against SARS-CoV-2, which would decrease the accuracy of our findings. In addition, because of the lack of details surrounding the timing of vaccination, our present study cannot account for the waning of immunity over the course of a pregnancy. One final limitation has to do with the effect that high levels of stress may have on a pregnant mother during a pandemic, particularly on mothers who have made the decision to defer vaccination against the advice of their physician. As authors we see no effective way to control for the effect of this stress on our outcomes. Nevertheless, our study provides various novel insights into potential influence of vaccination on various novel outcomes. Our study further emphasizes a need to increase the awareness about the SARS-CoV-2 infection and the safety of vaccine administration to pregnant women, through obstetricians and medical personnel.75.We performed our systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, Meta-analysis Of Observational Studies in Epidemiology (MOOSE), and the Cochrane handbook of systematic review and meta-analysis of interventionsWe searched six databases: PubMed, Scopus, Medline, Cochrane Library, and Web of Science for relevant observational studies conducted on COVID-19 vaccinated pregnant women by using a combination of Medical Subject Headings (MeSH) terms and keywords to formulate this strategy:  AND (Pregnancy OR pregnant OR gestation OR gravidity OR childbearing)). We searched all English language papers from each database’s inception until January 31st, 2022, followed by manual searching of citations of the shortlisted articles to identify any additional articles. The screening process was conducted in two phases according to the eligibility criteria and was performed in parallel by two investigators (GM and ATM). The first phase comprised screening of title and abstract, followed by the next phase of full-text screening based on inclusion and exclusion criteria, as mentioned in the next section. Any conflict about the eligibility of a specific study was resolved by involving a third investigator (SG).We included all studies conducted on pregnant women receiving COVID-19 vaccination of any mechanism of action approved by an accredited body. The eligibility criteria for the included studies were: (I) Population: vaccinated pregnant women. (II) Intervention: any COVID-19 Vaccine. (III) Comparator: unvaccinated pregnant women (IV) Outcomes: (a) Maternal: unassisted vaginal delivery, operative vaginal delivery, cesarean section, gestational diabetes, gestational hypertension, preeclampsia, placental abruption, postpartum hemorrhage (defined as >500cc blood loss), length of hospital stay at the time of delivery; (b) Neonatal: preterm delivery, 5-min Apgar score ≤7, first-trimester miscarriage, fetal abnormalities, neonatal intensive care unit admission, small for gestational age (defined as less than the 10th percentile weight at birth), and intrauterine growth restriction , (c) Immunological: maternal COVID-19 infection confirmed by COVID-19 by a polymerase chain reaction (PCR) test or with ICD-10 codes for confirmed COVID-19 at any time in the antepartum or postpartum period (defined as the entire pregnancy to 6 weeks postpartum), and vaccination antibody levels at delivery of both mother and infant, and (V) Study design: We included all observational studies including cohort and case-control studies. We excluded reviews, case reports, case series, studies with lack of comparable data, and studies that reported data on less than ten vaccinated pregnant women. We further used only the latest dataset published by a group, to avoid duplication of samples.76.We extracted the information on study design, demographic and baseline characteristics of the study populations, including maternal age, gestational age, BMI, gravidity, parity, the incidence of pre-gestational diabetes, and pre-gestational hypertension. In addition, we extracted the data for our selected outcomes for statistical analysis (See outcomes in the section on Inclusion and Exclusion criteria). We used the National Heart, Lung, and Blood Institute (NHLB) tool for the quality assessment tool of observational studies, including 14 domains assessing the overall quality of the studiesP-value for overall effect was <0.05. In general, we employed a fixed-effects model as a default to pool the individual effect estimates (OR or MD). A random-effects model was only used for heterogeneous findings (if Phet < 0.1 as well as I2 > 50%)77. We conducted sensitivity analysis by the “leave-one-out” method to identify sources of heterogeneity and reliability of our findings77.We analyzed the extracted outcomes using Review Manager Software (Version 5.0). Dichotomous outcomes were meta-analyzed using Odds Ratio (OR) and continuous data using Mean Difference (MD). We used forest plots to show individual and pooled effect estimates with 95% confidence intervals (CI). We performed the meta-analysis comparing vaccinated to unvaccinated pregnant women with no history of SARS-CoV-2 infection by using the Mantel-Haenszel for categorical outcomes and Inverse Variance for continuous outcomes, the results were considered significant if the Due to limited combinability in specific immunological outcomes, such as different titer measurement protocols, we qualitatively summarized the outcomes related to antibody levels as maternal serum antibody levels, umbilical cord sample antibody levels, and transfer ratios. A quantitative synthesis was not possible for those results. Also, we qualitatively compared these levels in vaccinated pregnant women to those in infected unvaccinated pregnant women, non-pregnant vaccinated women, and non-infected unvaccinated women. Finally, we studied the specific factors that influenced each outcome, including additional or “booster” dose administration, gestational vaccination time, and time elapsed from the first or second dose until delivery.In conclusion, we found that the administration of the COVID-19 vaccine to pregnant women effectively prevented future SARS-CoV-2 infection. It appears safe and seems to provide passive immunity to neonates. Administration of an additional or “booster” dose may increase the immune response and transplacental antibody transfer. As this data applies to an actively evolving pandemic, changes in the clinical scenario, including variations of the virus and changes in the immune status of affected populations will invariably limit how applicable this data is to the day-to-today prevention and treatment of COVID-19. In addition to being protective against SARS-CoV-2, the vaccine was associated with decreased odds of preterm delivery. Also, for reasons not entirely understood, our data shows that COVID-19 vaccination may also be associated with higher odds of cesarean section.Supplemental Material


Deep learning faces a significant challenge wherein the trained models often underperform when used with external test data sets. This issue has been attributed to spurious correlations between irrelevant features in the input data and corresponding labels. This study uses the classification of COVID-19 from chest x-ray radiographs as an example to demonstrate that the image contrast and sharpness, which are characteristics of a chest radiograph dependent on data acquisition systems and imaging parameters, can be intrinsic shortcuts that impair the model’s generalizability. The study proposes training certified shortcut detective models that meet a set of qualification criteria which can then identify these intrinsic shortcuts in a curated data set. This limits the translation and deployment of deep learning models for high-stakes tasks, such as in healthcare applications. This lesson was evident during the COVID-19 pandemic, where many machine learning models were developed, but very few performed well on real-world clinical tests6.Deep learning has been incredibly successful in object detection, image classification, and natural language processing over the past ten years due to its ability to learn complex features from data. However, despite its success on benchmark datasets, there are limitations and practical issues when using these models in real-world scenarios. A major challenge is poor generalizability, where performance significantly drops when applied to external datasets7. It has been discovered that poor model generalizability can be attributed to shortcut learning when the training dataset has hidden shortcuts, meaning there are spurious correlations between irrelevant image features and the corresponding training labels. This causes models to quickly pick up these spurious correlations instead of the desired image features, establishing incorrect connections between input image data and output labels. For instance, early studies have shown that deep learning models can differentiate chest x-rays from different hospitals and patient groups1. This suggests that different data sources and patient characteristics like gender, age, and race could also become shortcuts.The concept of shortcut learning has recently been explored in deep learning studies8 discovered that if COVID-19 positive and negative training data were collected from two different sources, the model would only learn the source label as a shortcut for prediction. As a result, the model would not have the desired prediction power in real-world clinical scenarios. The authors also found that the trained model used extrinsic image features, such as lead markers, for prediction, even though these markers only indicated the orientation of patients in x-ray image acquisitions and did not correspond to any disease features. Some suggestions have been made to remove these extrinsic shortcuts by a segmentation step9. However, even with these markers removed from the training dataset, some other shortcuts still existed in the segmented lung tissue-only training dataset10. As a result, the nearly perfect performance of the trained model9 is still not generalizable to real-world clinical datasets. The remaining shortcuts may be attributed to the inherent defining features of CXRs, such as image contrast and sharpness, which can vary from hospital to hospital due to different types of imaging systems, generations of x-ray imaging equipment, hardware components, image post-processing methods used by vendors, and imaging protocols used by technologists. All these factors can impact the digital representation of the acquired image data in terms of variations in image contrast and sharpness. To illustrate the issue of shortcut learning in real-world clinical scenarios, let’s take the example of COVID-19 classification using chest x-ray radiographs (CXRs). DeGrave et al. Unlike other shortcuts that have been previously studied, such as age, gender, race, and markers, which are extrinsic and can be removed through careful data collection and cleaning, contrast- and sharpness-related shortcuts are more difficult to detect and mitigate. This is because desired image features are also represented as image contrast and spatial correlations, which are similar to the features of contrast- and sharpness-related shortcuts. This entanglement between desired image features and shortcut features makes studying contrast and sharpness-related shortcuts particularly challenging. Consequently, these shortcuts are referred to as intrinsic shortcuts in this work.11 and expected gradient12, have been developed to identify relevant image features used by trained deep learning models for prediction, these methods are unable to detect intrinsic shortcuts within a curated training dataset prior to model training. Furthermore, studies have suggested that these methods may not be effective in diagnosing poor generalization performance of the model13.In order to develop an effective strategy for mitigating contrast- and sharpness-related shortcuts, it is necessary to first develop reliable methods for detecting their presence and severity within a carefully curated dataset. While post-hoc model interpretability methods, such as class activation mapsIn this paper, we present a novel approach for detecting contrast- and sharpness-related intrinsic shortcuts using certified shortcut detective models. Our approach involves establishing qualification standards for suspected intrinsic shortcuts, designing a training curriculum for training the shortcut detectives to detect these shortcuts, performing certification tests on the trained detectives, and finally deploying them to curated datasets to examine the suspected shortcuts. We applied this approach to the available COVID-19 datasets to assess their quality. Our results demonstrate the effectiveness of this approach in detecting and mitigating intrinsic shortcuts.14 chest x-ray dataset consists of 377,110 CXRs from 65,379 patients presenting to the Beth Israel Deaconess Medical Center Emergency Department between 2011–2016. In this work, 46,894 frontal-view (AP/PA) normal CXRs (cases with “No Finding” labels) were used to train shortcut detectives.MIMIC-CXRHF-train consisted of 8,733 COVID-19-positive CXRs from 4,383 patients and 16,584 COVID-19-negative CXRs from 8,733 patients; HF-test consisted of 695 COVID-19-positive CXRs from 526 patients and 8,878 COVID-19-negative CXRs from 6,081 patients.This is a privately curated COVID-19 CXR dataset from patients presenting to the Henry Ford Health between March 1, 2020, and October 31, 2020. The COVID-19-positive and COVID-19-negative cohorts are collected within the same time range, from the same hospitals, and labeled by their most recent RT-PCR test result seven days before or after the imaging study. For model training and internal testing, two data partitions are generated: 15. This dataset was collected from 11 hospitals in the Valencian Region, Spain, between February and April 2020. After data curation, the dataset consisted of 4,169 COVID-19-positive CXRs from 2,663 patients and 5,050 COVID-19-negative CXRs from 3,710 patients.This is a public COVID-19 CXR dataset collected in SpainThis is a privately curated COVID-19 CXR dataset. It includes consecutive patient cases from the University of Wisconsin Hospitals and Clinics  from March 2020 to September 2021. The dataset comprised 1,025 COVID-19-positive CXRs from 658 patients and 8,774 COVID-19-negative CXRs from 5,953 patients.https://data.midrc.org/, date accessed: December 7th, 2022).This is a large, multi-institution public COVID-19 CXR dataset curated and released by the Medical Imaging & Data Resource Center (MIDRC). A total of 6,453 COVID-19-positive CXRs from 5,199 patients and 20,072 COVID-19-negative CXRs from 9,947 patients were pulled from the MIDRC Data Commons , and 400 CXRs are included in the test dataset (COVIDx-test). .This is a public COVID-19 CXR dataset released by the COVID-Net Open Source Initiative17 and 1,000 real “No Finding” CXRs from the MIMIC dataset. The RoentGen model, which is trained using the MIMIC dataset, is able to generate visually convincing synthetic CXRs with different pathologies. To generate the synthetic CXRs used in this work, a text prompt of “No finding” was used as the input, only frontal view CXRs are included.This dataset contains 943 synthetic CXRs generated by the RoentGen modelAn overview of the shortcut detective training and certification process is shown in To begin, 46,894 normal CXRs from the MIMIC dataset were selected and randomly divided into two equal groups: 23,447 of the CXRs were assigned as the positive class (“1”) while the rest were assigned as the negative class (“0”).Then, to construct the training dataset for the shortcut detective, the image contrast or the image sharpness of the positive class were adjusted using the approach shown in Subsequently, shortcut detectives  were trained using the constructed training datasets with contrast or sharpness shortcuts. Details of the training are discussed in the following section and in 18, where a model trained on this dataset demonstrated consistent test performance on various external COVID-19 clinical test datasets. For the second examination, known shortcuts are integrated into the COVID-positive class or COVID-negative class of the HF-train dataset using the same procedures outlined in To assess the efficacy of the shortcut detectives on COVID-19 CXR dataset, two types of examinations are necessary. Firstly, when the shortcut detective is deployed on a COVID-CXR dataset without the corresponding shortcut, it should not be able to differentiate between the COVID-positive and COVID-negative classes. Hence, an Area Under the Receiver Operating Characteristics curve (AUC) close to 0.5 is expected. This examination is crucial to ensure that the image features utilized by the shortcut detectives are not interwoven with the original imaging task. Secondly, when the shortcut detective is applied to a COVID-CXR dataset with a known shortcut, it should demonstrate superior classification performance, ideally with an AUC close to 1. For the first examination, the HF-train dataset is utilized. As the positive and negative cohorts are gathered within the same timeframe and from the same hospitals, it is expected that no contrast and sharpness shortcut exists. This has also been corroborated recentlyFinally, if the trained shortcut detectives pass the two exams, i.e. AUC of close to 0.5 on the shortcut-free dataset and AUC of close to 1.0 on the shortcut-present dataset, they are referred to as certified shortcut detectives.For the MIMIC, HF, BIMCV, UW Health and MIDRC datasets, the original DICOM images are converted to 8-bit png format with a size of 224-by-224 using the default window level and window width. For the COVIDx dataset, images are directly resized to 224-by-224.19 classification tasks are investigated in this work. Although we cannot exhaust all the possible model architectures for this purpose, the models we investigated include classic and modern Convolutional Neural Networks (CNN) and the recently introduced Swin Transformer. These models vary in architectural design and complexity . For each model architecture, an ensemble of five individually trained models with different training-validation splits are used. More technical details on the model training are shown in To train the shortcut detectives, five different model architectures  that areHF-train dataset and COVIDx-train dataset and compared their generalizability using internal and external tests.Certified shortcut detectives are deployed to detect shortcuts in real-world datasets, including BIMCV, UW, MIDRC, COVIDx, and RoentGen-MIMIC. We also trained two COVID-19 classification models using The 95% confidence intervals (CI) for the AUC were calculated using the statistical software R (version 4.0.0) with the pROC package. CIs were calculated using the bootstrap method with 2000 bootstrap replicates.As shown in Using the certified shortcut detectives, we investigated several curated COVID-CXR datasets for possible shortcuts. UW Health is a single-site, privately curated dataset; BIMCV and MIDRC are both multi-institutional public datasets; COVIDx is the first open access COVID-CXR dataset made available by the experts in the computer science community.Similar to the detective certification process, for a COVID-CXR dataset where COVID-19-positive cases are assigned a label “1” and negative cases are given a label “0”, if the shortcut detective can differentiate the two classes (AUC significantly deviates from 0.50), it indicates the existence of a corresponding shortcut. For the RoentGen-MIMIC dataset, real CXRs are labelled as “1” and synthetic CXRs are labelled as “0”.The results presented in 3, shortcut learning in various NLP tasks25, and mitigation strategies for domain-knowledge agnostic models26. Notably, it has been observed that convolutional neural networks tend to rely on content with high spatial frequency or strong local correlations to establish connections between input and labels in CV and NLP28. However, it remains unclear whether these observations can be extended to medical diagnosis tasks, where clinical datasets have distinct characteristics from those in ImageNet. Therefore, studying shortcut learning for well-defined, clinically relevant tasks using real-world clinical datasets is crucial for medical AI applications.Shortcut learning has been a topic of interest in the machine learning community, particularly in computer vision (CV) and natural language processing (NLP). Researchers have explored shortcut learning behavior from different perspectives, such as underspecificationIn this study, we demonstrated that acquisition-dependent attributes (ADAs), such as image contrast and sharpness differences arising from the entire image generation pipeline, can serve as intrinsic shortcuts during clinical diagnosis learning tasks. Inadequate quality control procedures during data collection can allow these shortcuts to inadvertently infiltrate the curated dataset. If shortcuts contaminate the dataset, neural networks can easily exploit them during training, thereby impairing their ability to generalize to other real-world datasets.Thus, it is imperative to identify possible shortcuts in the training dataset prior to model development. In this study, we present a methodical framework for training and validating shortcut detectives for chest X-ray classification, with emphasis on image contrast and sharpness - two essential intrinsic characteristics of chest X-ray images. However, it should be noted that these are not the only possible shortcuts that may exist in chest X-ray datasets. If other intrinsic shortcuts are suspected in a collected dataset, the general framework presented in this work can be utilized to construct similar shortcut detectives and identify alleged intrinsic shortcuts.Once the intrinsic shortcuts are identified, it is essential to develop strategies to mitigate their impact on the learned models. One possible approach is to develop standardization and normalization techniques for image contrast and sharpness to adjust these attributes without affecting the disease features. Alternatively, examining proven intrinsic shortcut-free datasets, such as the baseline dataset  and the three additional datasets  shown to be free of intrinsic shortcuts in this study, can provide further insight on how to avoid these shortcuts in the data curation process. However, it is worth noting that this is a limitation of the present work, and future research should investigate the development of mitigation strategies for the identified intrinsic shortcuts.Supplement 1