Individual Participant Data Meta-analysis Research Articles

Laryngeal features in Lipoid proteinosis: a systematic review and meta-analysis of individual participant data.

Lipoid proteinosis (LP) or Urbach-Wiethe disease (OMIM 247100) is a rare syndrome characterised by early vocal folds infiltration and subsequent multi-organ involvement. LP is often unrecognised and its associated hoarseness is overlooked. The main objective of the study was to investigate hoarseness in LP and implement a diagnosis among otolaryngologists. PubMed/MEDLINE and OMIM databases were systematically searched. Authors concentrated the search on published articles starting from the discovery of the pathogenesis of LP by Hamada et al. in 2002. Only cases in which a diagnosis was reported both clinically and through biopsy and/or genetic molecular testing were included. Characteristics of the LP cases were extracted from each included study. Results were obtained through Generalized Estimating Equations. The search strategy yielded 217 articles, of which 74 (34.1%) met the selection criteria. A total of 154 cases were included. Hoarseness was described in all LP cases and clearly stated as the onset symptom in 68.8%. The onset was on average at 19months of age (CI: 3.00-20.00), while the mean age at diagnosis was 15years (CI: 10.00-30.00). Therefore, the diagnostic delay amounted to 13.42years (CI: 8.00-23.83). Hoarseness alone was responsible for an LP diagnosis in only 14.3% of cases. In 43.5% of cases, genetic analysis of the ECM1 gene was performed and exon 6 was the most frequently altered portion. Analysing the largest number of published cases, the study underlined that hoarseness is the key symptom for diagnosing LP since early childhood, though frequently overlooked.

Obesity in women with polycystic ovary syndrome -an individual participant data meta-analysis of well characterised, unselected populations

Obesity in women with polycystic ovary syndrome -an individual participant data meta-analysis of well characterised, unselected populations

150 Development of a leaky gut model: Meta-analysis of plasma and fecal markers of leaky gut

Abstract Intestinal integrity can be compromised in livestock and poultry species during stress events, including off-feed events. To develop a leaky gut model, weanling barrows 26 to 28 d old [n = 307; Duroc terminal line Fast genetics, initial body weight (BW) = 5.90 ± 0.47 kg), were used in a total of 6 randomized complete block experiments at the NutriQuest modeling center (Fergus Falls, MN). All trials included positive control (PC) and negative control (NC) treatments. The other treatments evaluated (n = 8) were various strains and levels of direct-fed microbial (DFM) products. With the exception of PC, all treatments had complete 24-h feed restriction (FR) approximately 18 d after arrival. Pigs assigned to PC had ad libitum access to feed. Pigs were housed 3 pigs per pen in 1 of 30 pens, and all pigs were fed a common high-quality basal diet. For 3 trials, pigs received Excede (Zoetis; Parsipanny, NJ) IM upon arrival and were provided gentamycin via water for 3 d post-arrival. For 3 trials, no prophylactic antibiotics were administered. Eighteen days post-arrival, fecal and plasma samples were collected from all pigs and feed was removed from FR pens. After 24 h, plasma and fecal samples were collected from all pigs, and one-half of the pigs per trial were harvested for tissue collection. Four days after FR, samples were collected similarly, and the remaining pigs were harvested. Plasma samples were analyzed for LPS binding protein concentrations (LBP), and fecal samples were analyzed for myeloperoxidase (MPO) concentrations. Data from the PC (n = 90) and NC (n = 92) treatments only were analyzed as Individual Participant Data meta-analysis using PROC MIXED of SAS. Data from all pigs (n = 307) were analyzed using PROC REG of SAS with forward step-wise selection to determine relationships between response variables. Plasma LBP concentrations did not differ between PC and NC 24 h after FR (P = 0.14). However, change in LBP concentrations and the ratio of LBP immediately before and after FR, differed between PC and NC (P < 0.001). For NC, LBP concentrations decreased, and for PC, LBP concentrations increased (Table 1). There was no effect of treatment on fecal MPO concentrations. Using the broader dataset (n = 307), variables that were predictive of plasma LBP concentrations immediately following FR were trial (P < 0.001), treatment (P < 0.001), and fecal MPO concentrations (P < 0.05). Variables that were predictive of change in LBP concentrations before and after FR were trial (P < 0.001), treatment (P < 0.001), and initial BW (P < 0.01). These data, taken with data presented in a companion abstract on ileal tight junction gene expression, suggest that plasma LBP concentrations immediately following a FR event are a useful marker of leaky gut. Fecal MPO concentrations do not consistently respond to FR.

Effectiveness of preventive treatment among different age groups and Mycobacterium tuberculosis infection status: a systematic review and individual-participant data meta-analysis of contact tracing studies.

Tuberculosis is a preventable disease. However, there is debate regarding which individuals would benefit most from tuberculosis preventive treatment and whether these benefits vary in settings with a high burden and low burden of tuberculosis. We aimed to compare the effectiveness of tuberculosis preventive treatment in exposed individuals of differing ages and Mycobacterium tuberculosis infection status while considering tuberculosis burden of the settings. In this systematic review and individual-participant meta-analysis, we investigated the development of incident tuberculosis in people closely exposed to individuals with tuberculosis. We searched for studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase. We restricted our search to cohort studies; case-control studies and outbreak reports were excluded. Two reviewers evaluated titles, abstracts, and full text articles for eligibility. At each stage, two reviewers discussed discrepancies and re-evaluated articles until a consensus was reached. Individual-participant data and a pre-specified list of variables, including characteristics of the exposed contact, the index patient, and environmental characteristics, were requested from authors of all eligible studies; contacts exposed to a drug-resistant tuberculosis index patient were excluded. The primary study outcome was incident tuberculosis. We estimated adjusted hazard ratios (aHRs) for incident tuberculosis with mixed-effects Cox regression models with a study-level random effect. We estimated the number-needed-to-treat (NNT) to prevent one person developing tuberculosis. Propensity score matching procedures were used in all analyses. This study is registered with PROSPERO (CRD42018087022). After screening 25 358 records for eligibility, 439 644 participants from 32 cohort studies were included in the individual-participant data meta-analysis. Participants were followed for 1 396 413 person-years (median of 2·7 years [IQR 1·3-4.4]), during which 2496 people were diagnosed with incident tuberculosis. Overall, effectiveness of preventive treatment was 49% (aHR 0·51 [95% CI 0·44-0·60]). Participants with a positive tuberculin-skin-test (TST) or IFNγ release assay (IGRA) result at baseline benefitted from greater protection, regardless of age (0·09 [0·05-0·17] in children younger than 5 years, 0·20 [0·15-0·28] in individuals aged 5-17 years, and 0·17 [0·13-0·22] in adults aged 18 years and older). The effectiveness of preventive treatment was greater in high-burden (0·31 [0·23-0·40]) versus low-burden (0·58 [0·47-0·72]) settings. The NNT ranged from 9 to 34 depending on age among participants with a positive TST or IGRA in both high-burden and low-burden settings; among all contacts (regardless of TST or IGRA test result), the NNT ranged from 29 to 43 in high-burden settings and 213 to 455 in low-burden settings. Our findings suggest that a risk-targeted strategy prioritising contacts with evidence of M tuberculosis infection might be indicated in low-burden settings, and a broad approach including all contacts should be considered in high-burden settings. Preventive treatment was similarly effective among contacts of all ages. None.

The mediating role of health behaviors in the association between depression, anxiety and cancer incidence: an individual participant data meta-analysis.

Although behavioral mechanisms in the association among depression, anxiety, and cancer are plausible, few studies have empirically studied mediation by health behaviors. We aimed to examine the mediating role of several health behaviors in the associations among depression, anxiety, and the incidence of various cancer types (overall, breast, prostate, lung, colorectal, smoking-related, and alcohol-related cancers). Two-stage individual participant data meta-analyses were performed based on 18 cohorts within the Psychosocial Factors and Cancer Incidence consortium that had a measure of depression or anxiety (N = 319 613, cancer incidence = 25 803). Health behaviors included smoking, physical inactivity, alcohol use, body mass index (BMI), sedentary behavior, and sleep duration and quality. In stage one, path-specific regression estimates were obtained in each cohort. In stage two, cohort-specific estimates were pooled using random-effects multivariate meta-analysis, and natural indirect effects (i.e. mediating effects) were calculated as hazard ratios (HRs). Smoking (HRs range 1.04-1.10) and physical inactivity (HRs range 1.01-1.02) significantly mediated the associations among depression, anxiety, and lung cancer. Smoking was also a mediator for smoking-related cancers (HRs range 1.03-1.06). There was mediation by health behaviors, especially smoking, physical inactivity, alcohol use, and a higher BMI, in the associations among depression, anxiety, and overall cancer or other types of cancer, but effects were small (HRs generally below 1.01). Smoking constitutes a mediating pathway linking depression and anxiety to lung cancer and smoking-related cancers. Our findings underline the importance of smoking cessation interventions for persons with depression or anxiety.

Meta-analyses in cholestatic pregnancy: The outstanding clinical questions

Reports of adverse pregnancy outcomes associated with maternal pruritus and liver impairment have circulated since the 1800s, yet the precise diagnosis and management of intrahepatic cholestasis of pregnancy have varied markedly. Recent evidence, including that from individual participant data meta-analyses, has provided an evidence that brings us closer to standardised, and optimal, management of the condition. Based upon increased adverse perinatal outcomes with higher bile acid concentrations, disease management should be according to severity (defined by peak bile acid concentration) in order to recommend appropriate gestation of birth. Similarly, the reduced spontaneous preterm birth rate for patients receiving ursodeoxycholic acid treatment suggests potential benefit for the treatment of patients with moderate-severe disease.

Lifestyle and incident dementia: A COSMIC individual participant data meta‐analysis

The LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics. We combined data from 21 prospective cohorts across six continents (N=31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis. A one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed. Modifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups. A two-step individual participant data meta-analysis was conducted. This was done at a global scale using data from 21 ethno-regionally diverse cohorts. The association between a modifiable dementia risk score and dementia was examined. The association was modified by geographical region and age at baseline. Yet, modifiable dementia risk and protective factors appear relevant in all investigated groups and regions.

Elevated skull fractures: an institutional experience and individual participant data meta-analysis.

Elevated skull fracture (ESF) is a rare but potentially life-threatening type of skull fracture. The literature on this topic is relatively sparse. Herein, we conducted a meta-analysis of all the patients reported in the literature with ESFs with respect to their clinical management to better inform practice. On 20th of January 2023, we conducted a systematic search of literature to find all published cases of ESF. We also conducted a retrospective review of ESF cases from our institution. The data collection and analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. After screening, 28 studies met the inclusion criteria. A total of 104 individual patients were included in the meta-analysis, with a median age of 24 years and 85.7% of whom were males. 11 patients (11.2%) had an unfavorable outcome while 37 (35.2%) had one or more complications. We found that GCS on admission is an independent predictor of poor outcome in ESF (odds ratio (95% confidence interval) = 1.605 (1.110-2.315), p value = 0.012). Regarding complications, dural injury (odds ratio (95% confidence interval) = 66.667 (7.407-500.00), p value < 0.001) and multiple bone involvement (odds ratio (95% confidence interval) = 6.849 (2.127-22.222), p value = 0.001) were independent predictors of complication. ESFs represent a rare yet consequential form of cranial injury, carrying potentially life-threatening implications if not promptly addressed. In this study, we present the meta-analysis of outcomes and complications within this patient cohort, offering a comprehensive synthesis of existing literature on this pathology. However, further investigation is imperative to provide higher-quality evidence and address lingering uncertainties in the classification and management of ESFs.

Application of causal inference methods in individual-participant data meta-analyses in medicine: addressing data handling and reporting gaps with new proposed reporting guidelines

Observational data provide invaluable real-world information in medicine, but certain methodological considerations are required to derive causal estimates. In this systematic review, we evaluated the methodology and reporting quality of individual-level patient data meta-analyses (IPD-MAs) conducted with non-randomized exposures, published in 2009, 2014, and 2019 that sought to estimate a causal relationship in medicine. We screened over 16,000 titles and abstracts, reviewed 45 full-text articles out of the 167 deemed potentially eligible, and included 29 into the analysis. Unfortunately, we found that causal methodologies were rarely implemented, and reporting was generally poor across studies. Specifically, only three of the 29 articles used quasi-experimental methods, and no study used G-methods to adjust for time-varying confounding. To address these issues, we propose stronger collaborations between physicians and methodologists to ensure that causal methodologies are properly implemented in IPD-MAs. In addition, we put forward a suggested checklist of reporting guidelines for IPD-MAs that utilize causal methods. This checklist could improve reporting thereby potentially enhancing the quality and trustworthiness of IPD-MAs, which can be considered one of the most valuable sources of evidence for health policy.

Moderators of treatment effect of non-steroidal anti-inflammatory drugs for patients with (sub) acute low back pain: Protocol for a systematic review with individual participant data meta-analysis

A Cochrane review found that non-steroidal anti-inflammatory drugs (NSAIDs) are slightly more effective than placebo on acute and subacute low back pain (LBP) outcomes (pain intensity, disability, and global improvement). Our objectives are: (1) to assess the overall treatment effect of NSAIDs in adults with acute and subacute LBP; (2) to identify the moderation of baseline patients’ characteristics on treatment effect. We will conduct a systematic search of RCTs on effectiveness of NSAIDs compared with placebo in adults with non-chronic LBP in Medline ALL, Embase, Cochrane Central Register of Controlled Trials*. We will screen the records after January 2020, and include eligible RCTs before January 2020 screened by the Cochrane review mentioned above. Our primary outcomes are pain intensity, disability, and health-related quality of life, secondary outcomes are adverse events. Our IPD dataset will consist of the information on each eligible trial characteristics and included variables according to a predefined coding scheme. We will assess risk-of-bias of included RCTs with the Cochrane Risk Of Bias (RoB)-2 assessment tool. We will perform power calculations with closed-form solutions and prioritize a one-stage approach for IPD-MA. For reporting the results, we will adhere to the PRISMA-IPD statement.

Plasma fibrinogen and risk of vascular recurrence after ischaemic stroke: An individual participant and summary-level data meta-analysis of 11 prospective studies.

Inflammation is an emerging target for secondary prevention after stroke and randomised trials of anti-inflammatory therapies are ongoing. Fibrinogen, a putative pro-inflammatory marker, is associated with first stroke, but its association with major adverse cardiovascular events (MACE) after stroke is unclear. We did a systematic review investigating the association between fibrinogen and post-stroke vascular recurrence. Authors were invited to provide individual-participant data (IPD) and where available we did within-study multivariable analyses with adjustment for cardiovascular risk factors and medications. Adjusted summary-level data was extracted from published reports from studies that did not provide IPD. We pooled risk ratios (RR) by random-effects meta-analysis by comparing supra-median with sub-median fibrinogen levels and performed pre-specified subgroup analysis according to timing of phlebotomy after the index event. Eleven studies were included (14,002 patients, 42,800 follow-up years), of which seven provided IPD. Fibrinogen was associated with recurrent MACE on unadjusted (RR 1.35, 95% CI 1.17-1.57, supra-median vs sub-median) and adjusted models (RR 1.21, 95% CI 1.06-1.38). Fibrinogen was associated with recurrent stroke on univariate analysis (RR 1.19, 95% CI 1.03-1.39), but not after adjustment (RR 1.11, 95% CI 0.94-1.31). The association with recurrent MACE was consistently observed in patients with post-acute (⩾14 days) fibrinogen measures (RR 1.29, 95% CI 1.16-1.45), but not in those with early phlebotomy (<14 days) (RR 0.98, 95% CI 0.82-1.18) (Pinteraction = 0.01). Similar associations were observed for recurrent stroke. Fibrinogen was independently associated with recurrence after stroke, but the association was modified by timing of phlebotomy. Fibrinogen measurements might be useful to identify patients who are more likely to derive benefit from anti-inflammatory therapies after stroke.

Analysis of Serum Free Thyroxine Concentrations in Healthy Term Neonates Underlines Need for Local and Laboratory-Specific Reference Interval: A Systematic Review and Meta-Analysis of Individual Participant Data.

Background: Initial evaluation of the hypothalamus-pituitary-thyroid axis is done by measuring serum free thyroxine (fT4) and thyrotropin concentrations. For correct interpretation of these measurements, reliable age-specific reference intervals (RIs) are fundamental. Since neonatal fT4 RIs conforming to the Clinical and Laboratory Standards Institute guidelines are not available for all assays, we set out to create literature-based uniform age-specific neonatal fT4 RIs that may be used for every assay. Methods: For meta-analysis of individual participant fT4 concentrations, we systematically searched MEDLINE and Embase (search date December 6, 2023; PROSPERO registration CRD42016041871). We searched for studies reporting fT4 concentrations in healthy term newborns aged 2-27 days, born to mothers without thyroid disease in iodine-sufficient regions. Authors were invited to supply data. Due to standardization differences between assays, data could not be combined for meta-analysis directly, and we attempted to normalize the data using two distinct methods. Results: We obtained 4206 fT4 concentrations from 20 studies that used 13 different assays from 6 manufacturers. First, we set out to normalize fT4 data using the mean and standard deviation of (assay-specific) adult RIs. fT4 concentrations were transformed into Z-scores, assuming a normal distribution. Using a linear mixed-effects model (LMM), we still found a significant difference between fT4 concentration across studies (p < 0.001), after this normalization. As a second approach, we normalized the fT4 concentrations using data from a method/assay comparison study. We used the relationship between the Cobas assay and the other assays as a reference point to convert all values to Cobas values. However, this method also failed to produce consistent results, with significant differences between the normalized data (LMM p < 0.001). Conclusions: We conclude that our attempts at normalizing fT4 assay results were unsuccessful. Confounders related to our unsuccessful analysis may be assay related and/or biological. These findings have significant implications for patient care, since relying on RIs from literature may result in erroneous interpretation of results. Therefore, we strongly recommend to establish local RIs for accurate interpretation of serum fT4 concentrations in neonates.

370 Is There an Optimal Surgical Approach in Degenerative Cervical Myelopathy?: An Individual Participant Data Meta-Analysis

INTRODUCTION: Contradictions exist about impact of anterior vs. posterior surgical approach on outcomes of degenerative cervical myelopathy (DCM). METHODS: Individual patient data of subjects who underwent surgery for DCM was identified from a pooled dataset of the AO Spine CSM-North America, CSM-International, and CSM-Protect clinical studies. Primary outcomes were changes in short form 36 Physical Component Summary score (SF36-PCS) and mJOA score at 12 months. Secondary outcomes were change in total Neck Disability Index (NDI) score and SF36 Mental Component Summary score (SF36-MCS). Two comparison cohorts were created: i) anterior surgery and ii) posterior surgery. One-stage mixed-effects meta-analysis with study and treatment exposure as random effects was performed and reported with mean differences and 95% confidence intervals. A subgroup analysis planned a priori in mild DCM patients (mJOA 15-17) was performed. RESULTS: A total of 979 patients met eligibility criteria. Patients who had anterior decompressive surgery experienced greater improvements at 1yr of follow-up than those who underwent posterior decompressive surgery in SF36-PCS score (adjusted MD 1.57 [95% CI 0.11 to 3.03], p = 0.0348) and NDI score (adjusted MD 3.32 [95% CI 0.58 to 6.05], p = 0.0172). A greater proportion of patients that underwent anterior surgery achieved clinically important recovery of their NDI (OR 1.49 [95% CI 1.15 to 1.93], p = 0.002; aOR 1.46 [95% CI 1.08 to 1.96], p = 0.013) and SF36-PCS scores at 1yr (OR 1.45 [95% CI 1.12 to 1.88], p = 0.004, aOR 1.34 [95% CI 1.00 to 1.80], p = 0.052). In patients with mild DCM (n = 186), patients who underwent anterior decompressive surgery experienced greater improvements in SF36-PCS score, mJOA score, and Neck Disability Index score than posterior surgical patients. CONCLUSIONS: Anterior surgical decompression for DCM is associated with greater improvements in 1yr patient-reported outcomes than posterior surgical decompression.

Rates and causes of death after release from incarceration among 1 471 526 people in eight high-income and middle-income countries: an individual participant data meta-analysis

Rates and causes of death after release from incarceration among 1 471 526 people in eight high-income and middle-income countries: an individual participant data meta-analysis

1075 The Effect of Regional Procedural Preference on Outcomes After Posterior Decompression for Degenerative Cervical Myelopathy: Individual Participant Data Meta-Analysis of a Prospective, Multinational Dataset of 1047 Cases

INTRODUCTION: There is considerable debate regarding the relative effectiveness of laminoplasty vs. laminectomy and fusion for posterior surgical decompression of degenerative cervical myelopathy (DCM). METHODS: Subjects with DCM that underwent posterior decompression was derived from three independent, prospective, multicentre clinical trials (CSM-NA, CSM-I, CSM-Protect). Primary endpoint was change in SF36-PCS (minimum clinically important difference [MCID] 4) at 1yr compared to pre-operative assessment. Secondary endpoints were change in mJOA (MCID 2) score, Neck Disability Index (NDI; MCID 15) score, NDI Pain Intensity score, and SF36-MCS (MCID 4) score. Two comparison cohorts were created: i) laminoplasty (LP) and ii) laminectomy and fusion (LF). One-stage hierarchical mixed-effects meta-analyses with study and treatment exposure as random effects were performed. As subgroup analysis, the influence of procedural volume between LP-predominant sites, LF-predominant sites, and volume-equivalent sites was investigated. RESULTS: From a total of 1047 patients with DCM, 369 patients met eligibility criteria. There was geographic variability in surgical choice with higher rates of laminectomy and fusion in Brazil and Canada and higher laminoplasty rates in Japan and India. USA had similar rates of LF and LP. When compared to LF-predominant sites, LP-predominant sites achieved greater rates of MCID for mJOA at 1yr (85.4% v. 68.7%, p=0.036) with their predominant technique. There were no significant differences in MCID rates of NDI, SF36-PCS, or SF36-MCS. When comparing LF-predominant and LP-predominant sites with USA, a volume equivalent site, there were no significant differences in MCID rates of all outcomes. CONCLUSIONS: Sites that primarily used LP achieved greater rate of MCID in mJOA with laminoplasty than laminectomy with fusion from primarily LF sites. This suggests that experience with either LP or LF can drive outcomes which has interesting healthcare delivery implications.

Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis

Previous meta-analyses of summary data from randomised controlled trials have shown that statin therapy increases the risk of diabetes, but less is known about the size or timing of this effect, or who is at greatest risk. We aimed to address these gaps in knowledge through analysis of individual participant data from large, long-term, randomised, double-blind trials of statin therapy. We conducted a meta-analysis of individual participant data from randomised controlled trials of statin therapy that participated in the CTT Collaboration. All double-blind randomised controlled trials of statin therapy of at least 2 years' scheduled duration and with at least 1000 participants were eligible for inclusion in this meta-analysis. All recorded diabetes-related adverse events, treatments, and measures of glycaemia were sought from eligible trials. Meta-analyses assessed the effects of allocation to statin therapy on new-onset diabetes (defined by diabetes-related adverse events, use of new glucose-lowering medications, glucose concentrations, or HbA1c values) and on worsening glycaemia in people with diabetes (defined by complications of glucose control, increased use of glucose-lowering medication, or HbA1c increase of ≥0·5%). Standard inverse-variance-weighted meta-analyses of the effects on these outcomes were conducted according to a prespecified protocol. Of the trials participating in the CTT Collaboration, 19 trials compared statin versus placebo (123 940 participants, 25 701 [21%] with diabetes; median follow-up of 4·3 years), and four trials compared more versus less intensive statin therapy (30 724 participants, 5340 [17%] with diabetes, median follow-up of 4·9 years). Compared with placebo, allocation to low-intensity or moderate-intensity statin therapy resulted in a 10% proportional increase in new-onset diabetes (2420 of 39 179 participants assigned to receive a statin [1·3% per year] vs 2214 of 39 266 participants assigned to receive placebo [1·2% per year]; rate ratio [RR] 1·10, 95% CI 1·04-1·16), and allocation to high-intensity statin therapy resulted in a 36% proportional increase (1221 of 9935 participants assigned to receive a statin [4·8% per year] vs 905 of 9859 participants assigned to receive placebo [3·5% per year]; 1·36, 1·25-1·48). For each trial, the rate of new-onset diabetes among participants allocated to receive placebo depended mostly on the proportion of participants who had at least one follow-up HbA1c measurement; this proportion was much higher in the high-intensity than the low-intensity or moderate-intensity trials. Consequently, the main determinant of the magnitude of the absolute excesses in the two types of trial was the extent of HbA1c measurement rather than the proportional increase in risk associated with statin therapy. In participants without baseline diabetes, mean glucose increased by 0·04 mmol/L with both low-intensity or moderate-intensity (95% CI 0·03-0·05) and high-intensity statins (0·02-0·06), and mean HbA1c increased by 0·06% (0·00-0·12) with low-intensity or moderate-intensity statins and 0·08% (0·07-0·09) with high-intensity statins. Among those with a baseline measure of glycaemia, approximately 62% of new-onset diabetes cases were among participants who were already in the top quarter of the baseline distribution. The relative effects of statin therapy on new-onset diabetes were similar among different types of participants and over time. Among participants with baseline diabetes, the RRs for worsening glycaemia were 1·10 (1·06-1·14) for low-intensity or moderate-intensity statin therapy and 1·24 (1·06-1·44) for high-intensity statin therapy compared with placebo. Statins cause a moderate dose-dependent increase in new diagnoses of diabetes that is consistent with a small upwards shift in glycaemia, with the majority of new diagnoses of diabetes occurring in people with baseline glycaemic markers that are close to the diagnostic threshold for diabetes. Importantly, however, any theoretical adverse effects of statins on cardiovascular risk that might arise from these small increases in glycaemia (or, indeed, from any other mechanism) are already accounted for in the overall reduction in cardiovascular risk that is seen with statin therapy in these trials. These findings should further inform clinical guidelines regarding clinical management of people taking statin therapy. British Heart Foundation, UK Medical Research Council, and Australian National Health and Medical Research Council.

Estimating individualized treatment effects using an individual participant data meta-analysis

BackgroundOne key aspect of personalized medicine is to identify individuals who benefit from an intervention. Some approaches have been developed to estimate individualized treatment effects (ITE) with a single randomized control trial (RCT) or observational data, but they are often underpowered for the ITE estimation. Using individual participant data meta-analyses (IPD-MA) might solve this problem. Few studies have investigated how to develop risk prediction models with IPD-MA, and it remains unclear how to combine those methods with approaches used for ITE estimation. In this article, we compared different approaches using both simulated and real data with binary and time-to-event outcomes to estimate the individualized treatment effects from an IPD-MA in a one-stage approach.MethodsWe compared five one-stage models: naive model (NA), random intercept (RI), stratified intercept (SI), rank-1 (R1), and fully stratified (FS), built with two different strategies, the S-learner and the T-learner constructed with a Monte Carlo simulation study in which we explored different scenarios with a binary or a time-to-event outcome. To evaluate the performance of the models, we used the c-statistic for benefit, the calibration of predictions, and the mean squared error. The different models were also used on the INDANA IPD-MA, comparing an anti-hypertensive treatment to no treatment or placebo (N=40237\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$N = 40\\,237$$\\end{document}, 836 events).ResultsSimulation results showed that using the S-learner led to better ITE estimation performances for both binary and time-to-event outcomes. None of the risk models stand out and had significantly better results. For the INDANA dataset with a binary outcome, the naive and the random intercept models had the best performances.ConclusionsFor the choice of the strategy, using interactions with treatment (the S-learner) is preferable. For the choice of the method, no approach is better than the other.

Ticagrelor or Clopidogrel Monotherapy vs Dual Antiplatelet Therapy After Percutaneous Coronary Intervention

Among patients undergoing percutaneous coronary intervention (PCI), it remains unclear whether the treatment efficacy of P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) depends on the type of P2Y12 inhibitor. To assess the risks and benefits of ticagrelor monotherapy or clopidogrel monotherapy compared with standard DAPT after PCI. MEDLINE, Embase, TCTMD, and the European Society of Cardiology website were searched from inception to September 10, 2023, without language restriction. Included studies were randomized clinical trials comparing P2Y12 inhibitor monotherapy with DAPT on adjudicated end points in patients without indication to oral anticoagulation undergoing PCI. Patient-level data provided by each trial were synthesized into a pooled dataset and analyzed using a 1-step mixed-effects model. The study is reported following the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data. The primary objective was to determine noninferiority of ticagrelor or clopidogrel monotherapy vs DAPT on the composite of death, myocardial infarction (MI), or stroke in the per-protocol analysis with a 1.15 margin for the hazard ratio (HR). Key secondary end points were major bleeding and net adverse clinical events (NACE), including the primary end point and major bleeding. Analyses included 6 randomized trials including 25 960 patients undergoing PCI, of whom 24 394 patients (12 403 patients receiving DAPT; 8292 patients receiving ticagrelor monotherapy; 3654 patients receiving clopidogrel monotherapy; 45 patients receiving prasugrel monotherapy) were retained in the per-protocol analysis. Trials of ticagrelor monotherapy were conducted in Asia, Europe, and North America; trials of clopidogrel monotherapy were all conducted in Asia. Ticagrelor was noninferior to DAPT for the primary end point (HR, 0.89; 95% CI, 0.74-1.06; P for noninferiority = .004), but clopidogrel was not noninferior (HR, 1.37; 95% CI, 1.01-1.87; P for noninferiority > .99), with this finding driven by noncardiovascular death. The risk of major bleeding was lower with both ticagrelor (HR, 0.47; 95% CI, 0.36-0.62; P < .001) and clopidogrel monotherapy (HR, 0.49; 95% CI, 0.30-0.81; P = .006; P for interaction = 0.88). NACE were lower with ticagrelor (HR, 0.74; 95% CI, 0.64-0.86, P < .001) but not with clopidogrel monotherapy (HR, 1.00; 95% CI, 0.78-1.28; P = .99; P for interaction = .04). This systematic review and meta-analysis found that ticagrelor monotherapy was noninferior to DAPT for all-cause death, MI, or stroke and superior for major bleeding and NACE. Clopidogrel monotherapy was similarly associated with reduced bleeding but was not noninferior to DAPT for all-cause death, MI, or stroke, largely because of risk observed in 1 trial that exclusively included East Asian patients and a hazard that was driven by an excess of noncardiovascular death.

Who benefits from indirect prevention and treatment of depression using an online intervention for insomnia? Results from an individual-participant data meta-analysis.

Major depressive disorder (MDD) is highly prevalent and burdensome for individuals and society. While there are psychological interventions able to prevent and treat MDD, uptake remains low. To overcome structural and attitudinal barriers, an indirect approach of using online insomnia interventions seems promising because insomnia is less stigmatized, predicts MDD onset, is often comorbid and can outlast MDD treatment. This individual-participant-data meta-analysis evaluated the potential of the online insomnia intervention GET.ON Recovery as an indirect treatment to reduce depressive symptom severity (DSS) and potential MDD onset across a range of participant characteristics. Efficacy on depressive symptom outcomes was evaluated using multilevel regression models controlling for baseline severity. To identify potential effect moderators, clinical, sociodemographic, and work-related variables were investigated using univariable moderation and random-forest methodology before developing a multivariable decision tree. IPD were obtained from four of seven eligible studies (N = 561); concentrating on workers with high work-stress. DSS was significantly lower in the intervention group both at post-assessment (d = -0.71 [95% CI-0.92 to -0.51]) and at follow-up (d = -0.84 [95% CI -1.11 to -0.57]). In the subsample (n = 121) without potential MDD at baseline, there were no significant group differences in onset of potential MDD. Moderation analyses revealed that effects on DSS differed significantly across baseline severity groups with effect sizes between d = -0.48 and -0.87 (post) and d = - 0.66 to -0.99 (follow-up), while no other sociodemographic, clinical, or work-related characteristics were significant moderators. An online insomnia intervention is a promising approach to effectively reduce DSS in a preventive and treatment setting.