Performance of the marginal structural models under various scenarios of incomplete marker's values: A simulation study

Marginal structural models (MSMs) have been proposed for estimating a treatment's effect, in the presence of time‐dependent confounding. We aimed to evaluate the performance of the Cox MSM in the presence of missing data and to explore methods to adjust for missingness. We simulated data with a continuous time‐dependent confounder and a binary treatment. We explored two classes of missing data: (i) missed visits, which resemble clinical cohort studies; (ii) missing confounder's values, which correspond to interval cohort studies. Missing data were generated under various mechanisms. In the first class, the source of the bias was the extreme treatment weights. Truncation or normalization improved estimation. Therefore, particular attention must be paid to the distribution of weights, and truncation or normalization should be applied if extreme weights are noticed. In the second case, bias was due to the misspecification of the treatment model. Last observation carried forward (LOCF), multiple imputation (MI), and inverse probability of missingness weighting (IPMW) were used to correct for the missingness. We found that alternatives, especially the IPMW method, perform better than the classic LOCF method. Nevertheless, in situations with high marker's variance and rarely recorded measurements none of the examined method adequately corrected the bias.     

Individual risk prediction: Comparing random forests with Cox proportional-hazards model by a simulation study

With big data becoming widely available in healthcare, machine learning algorithms such as random forest (RF) that ignores time-to-event information and random survival forest (RSF) that handles right-censored data are used for individual risk prediction alternatively to the Cox proportional hazards (Cox-PH) model. We aimed to systematically compare RF and RSF with Cox-PH. RSF with three split criteria [log-rank (RSF-LR), log-rank score (RSF-LRS), maximally selected rank statistics (RSF-MSR)]; RF, Cox-PH, and Cox-PH with splines (Cox-S) were evaluated through a simulation study based on real data. One hundred eighty scenarios were investigated assuming different associations between the predictors and the outcome (linear/linear and interactions/nonlinear/nonlinear and interactions), training sample sizes (500/1000/5000), censoring rates (50%/75%/93%), hazard functions (increasing/decreasing/constant), and number of predictors (seven, 15 including noise variables). Methods' performance was evaluated with time-dependent area under curve and integrated Brier score. In all scenarios, RF had the worst performance. In scenarios with a low number of events (⩽70), Cox-PH was at least noninferior to RSF, whereas under linearity assumption it outperformed RSF. Under the presence of interactions, RSF performed better than Cox-PH as the number of events increased whereas Cox-S reached at least similar performance with RSF under nonlinear effects. RSF-LRS performed slightly worse than RSF-LR and RSF-MSR when including noise variables and interaction effects. When applied to real data, models incorporating survival time performed better. Although RSF algorithms are a promising alternative to conventional Cox-PH as data complexity increases, they require a higher number of events for training. In time-to-event analysis, algorithms that consider survival time should be used.     

Quantitation of human immunodeficiency virus type 1 DNA forms with the second template switch in peripheral blood cells predicts disease progression independently of plasma RNA load

There are several forms of human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood T cells and lymph nodes in untreated HIV-1-infected individuals and in patients whose plasma HIV-1 RNA levels are suppressed by long-term combination antiretroviral therapy. However, it remains to be established whether the concentration of HIV-1 DNA in cells predicts the clinical outcome of HIV-1 infection. In this report, we measured the concentration of HIV-1 DNA forms which has undergone the second template switch (STS DNA) and 2-long-terminal-repeat DNA circles in peripheral blood mononuclear cell (PBMC) samples. To do this, we used molecular-beacon-based real-time PCR assays and studied 130 patients with hemophilia in the Multicenter Hemophilia Cohort Study. We assessed the influence of baseline HIV-1 STS DNA levels on the progression of HIV-1 disease in the absence of combination antiretroviral therapy by Kaplan-Meier and Cox regression analysis. Among the patients who progressed to AIDS, the median levels (interquartile ranges) of STS HIV-1 DNA in PBMC were significantly higher than those of patients who remained AIDS free during the 16 years of follow-up (1,017 [235 to 6,059] and 286 [31 to 732] copies per 10(6) PBMC, respectively; P < 0.0001). Rates of progression to death and development of AIDS varied significantly (log rank P < 0.001) by quartile distribution of HIV-1 STS DNA levels. After adjustment for age at seroconversion, baseline CD4(+) T-cell counts, plasma viral load, and T-cell-receptor excision circles, the relative hazards (RH) of death and AIDS were significantly increased with higher HIV-1 STS DNA levels (adjusted RH, 1.84 [95% confidence interval (CI), 1.30 to 2.59] and 2.62 [95% CI, 1.75 to 3.93] per 10-fold increase per 10(6) PBMC, respectively). HIV-1 STS DNA levels in each individual remained steady in longitudinal PBMC samples during 16 years of follow-up. Our findings show that the concentration of HIV-1 STS DNA in PBMC complements the HIV-1 RNA load in plasma in predicting the clinical outcome of HIV-1 disease. This parameter may have important implications for understanding the virological response to combination antiretroviral therapy.     

Virologic and Immunologic Response to cART by HIV-1 Subtype in the CASCADE Collaboration

Background

We aimed to compare rates of virologic response and CD4 changes after combination antiretroviral (cART) initiation in individuals infected with B and specific non-B HIV subtypes.

Methods

Using CASCADE data we analyzed HIV-RNA and CD4 counts for persons infected ≥1996, ≥15 years of age. We used survival and longitudinal modeling to estimate probabilities of virologic response (confirmed HIV-RNA <500 c/ml), and failure (HIV-RNA>500 c/ml at 6 months or ≥1000 c/ml following response) and CD4 increase after cART initiation.

Results

2003 (1706 B, 142 CRF02_AG, 55 A, 53 C, 47 CRF01_AE) seroconverters were included in analysis. There was no evidence of subtype effect overall for response or failure (p = 0.075 and 0.317, respectively) although there was a suggestion that those infected with subtypes CRF01_AE and A responded sooner than those with subtype B infection [HR (95% CI):1.37 (1.01–1.86) and 1.29 (0.96–1.72), respectively]. Rates of CD4 increase were similar in all subtypes except subtype A, which tended to have lower initial, but faster long-term, increases.

Conclusions

Virologic and immunologic response to cART was similar across all studied subtypes but statistical power was limited by the rarity of some non-B subtypes. Current antiretroviral agents seem to have similar efficacy in subtype B and most widely encountered non-B infections in high-income countries.     

Differences in HIV natural history among African and non-African seroconverters in Europe and seroconverters in sub-Saharan Africa

Introduction

It is unknown whether HIV treatment guidelines, based on resource-rich country cohorts, are applicable to African populations.

Methods

We estimated CD4 cell loss in ART-naïve, AIDS-free individuals using mixed models allowing for random intercept and slope, and time from seroconversion to clinical AIDS, death and antiretroviral therapy (ART) initiation by survival methods. Using CASCADE data from 20 European and 3 sub-Saharan African (SSA) cohorts of heterosexually-infected individuals, aged ≥15 years, infected ≥2000, we compared estimates between non-African Europeans, Africans in Europe, and Africans in SSA.

Results

Of 1,959 (913 non-Africans, 302 Europeans - African origin, 744 SSA), two-thirds were female; median age at seroconversion was 31 years. Individuals in SSA progressed faster to clinical AIDS but not to death or non-TB AIDS. They also initiated ART later than Europeans and at lower CD4 cell counts. In adjusted models, Africans (especially from Europe) had lower CD4 counts at seroconversion and slower CD4 decline than non-African Europeans. Median (95% CI) CD4 count at seroconversion for a 15–29 year old woman was 607 (588–627) (non-African European), 469 (442–497) (European - African origin) and 570 (551–589) (SSA) cells/µL with respective CD4 decline during the first 4 years of 259 (228–289), 155 (110–200), and 199 (174–224) cells/µL (p<0.01).

Discussion

Despite differences in CD4 cell count evolution, death and non-TB AIDS rates were similar across study groups. It is therefore prudent to apply current ART guidelines from resource-rich countries to African populations.     

Sunbathing,a possible risk factor of murine typhus infection in Greece

BackgroundThere are few studies about the presence of murine typhus in Greece. Our objective was to conduct a large scale retrospective investigation to determine the clinical and epidemiological features of patients diagnosed with murine typhus in Greece.Methodology/Principal findingsFrom 2012 to 2019 serum samples from hospitalized patients and outpatients throughout Greece suspected for murine typhus infection were tested by immunofluorescence assay for Rickettsia typhi. Immunofluorescence positive samples obtained since 2016 were also tested by qPCR targeting R. typhi. Clinical and epidemiological data were retrospectively collected for the patients with confirmed murine typhus. Overall, we tested 5,365 different patients and, in total, 174 patients from all geographic regions of Greece were diagnosed with murine typhus. The most frequently reported sign or symptom was fever (89%), followed by headache (84%) and rash (81%). The classical triad of fever, headache, and rash was present in 72% of patients during their illness. Severe infections with complications including acute renal failure or septic shock were not recorded. The majority of cases (81%) occurred during May–October and peaked in June and September. Most of patients (81%) infected in Athens, recalled that their only activity the last weeks before symptoms onset was swimming on the beach and 59% of them also reported an insect bite while sunbathing.Conclusions/SignificanceOur results may reflect the reemergence of murine typhus in Greece and we highlight the importance of awareness of this difficult-to-recognize undifferentiated febrile illness.