Other Distributions for a Continuous Response Aside the Normal Distribution in a Linear Regression Model.

In many instances, when one encounters a continuous response in model building, the normal distribution is often the preferred choice for the distribution of the response given the predictors. In particular, to some statisticians, the normal distribution is seen as the only distribution for a continuous response. Even when the assumption of normality is not met, various transformations are applied on the data so that it appears to be more nearly normal. This is sometimes not pleasant since, the model may no longer apply directly to the original scale of measurement, which is in most cases of interest. Likewise, in doing so, one tries to force the model framework and distributional assumption that may not be best for the data at hand. Aside transformations, other distributions exist and can equally (or even better) be used for a continuous response in a linear regression model. The theory in GLM extends the linear regression theory such that, a much broader family of distributions can be used for the error terms other than the normal distribution. In this paper, other continuous distributions are used to illustrate how they outperform the normal distribution in some instances. It is also shown that, occasionally (for a continuous response), the normal distribution does not seem to be a choice unless transformations are applied. As a tool for assessing which of the distributions provides the best fit, both AIC and BIC are used. To fit a GLM in SAS, the GENMOD procedure is used. In R, this can be accomplished by using the glm function. With these tools, only a handful of distributions can be used for the error terms. However, with the GAMLSS package in R, a number of distributions can be utilized. In using GAMLSS, the distribution of the response variable does not necessarily have to belong to the exponential family. Keywords: GLM, Exponential Family, AIC, BIC, GAMLSS

Assessing Univariate and Multivariate Normality, A Guide For Non-Statisticians

Most parametric methods rely on the assumption of normality. Results obtained from these methods are more powerful compared to their non-parametric counterparts. However for valid inference, the assumptions underlying the use of these methods should be satisfied. Many published statistical articles that make use of the assumption of normality fail to guarantee it. Hence, quite a number of published statistical results are presented with errors. As a way to reduce this, various approaches used in assessing the assumption of normality are presented and illustrated in this paper.   In assessing both univariate and multivariate normality, several methods have been proposed. In the univariate setting, the Q-Q plot, histogram, box plot, stem-and-leaf plot or dot plot are some graphical methods that can be used. Also, the properties of the normal distribution provide an alternative approach to assess normality. The Kolmogorov-Smirnov (K-S) test, Lilliefors corrected K-S test, Shapiro-Wilk test, Anderson-Darling test, Cramer-von Mises test, D'Agostino skewness test, Anscombe-Glynn kurtosis test, D'Agostino-Pearson omnibus test, and the Jarque-Bera test are also used to test for normality. However, Kolmogorov-Smirnov (K-S) test, Shapiro-Wilk test, Anderson-Darling test, and Cramer-von Mises test are widely used in practice and implemented in many statistical applications. For multivariate normal data, marginal distribution and linear combinations should also be normal. This provides a starting point for assessing normality in the multivariate setting. A scatter plot for each pair of variables together with a Gamma plot (Chi-squared Q-Q plot) is used in assessing bivariate normality. For more than two variables, a Gamma plot can still be used to check the assumption of multivariate normality. Among the many test proposed for testing multivariate normality, Royston's and Mardia's tests are used more often and are implemented in many statistical packages. When the normality assumption is not justifiable, techniques for non-normal data can be used. Likewise, transformation to near normality is another alternative. Keywords: Univariate normal, Multivariate normal, Q-Q plot, Gamma plot, Kolmogorov-Smirnov test, Shapiro-Wilk test, Mardia's test, Royston's test

The Influence of Apparent Temperature on Mortality in the Kintampo Health and Demographic Surveillance Area in the Middle Belt of Ghana: A Retrospective Time-Series Analysis.

Globally, studies have shown that diurnal changes in weather conditions and extreme weather events have a profound effect on mortality. Here, we assessed the effect of apparent temperature on all-cause mortality and the modifying effect of sex on the apparent temperature-mortality relationship using mortality and weather data archived over an eleven-year period. An overdispersed Poisson regression and distributed lag nonlinear models were used for this analysis. With these models, we analysed the relative risk of mortality at different temperature values over a 10-day lag period. By and large, we observed a nonlinear association between mean daily apparent temperature and all-cause mortality. An assessment of different temperature values over a 10-day lag period showed an increased risk of death at the lowest apparent temperature (18°C) from lag 2 to 4 with the highest relative risk of mortality (RR = 1.61, 95% CI: 1.2, 2.15, p value = 0.001) occurring three days after exposure. The relative risk of death also varied between males (RR = 0.31, 95% CI: 0.10, 0.94) and females (RR = 4.88, 95% CI: 1.40, 16.99) by apparent temperature and lag. On the whole, males are sensitive to both temperature extremes whilst females are more vulnerable to low temperature-related mortality. Accordingly, our findings could inform efforts at reducing temperature-related mortality in this context and other settings with similar environmental and demographic characteristics

Association of antidepressant drug use with outcome of patients with glioblastoma

Depressive symptoms are common among patients with glioblastoma, but patients are often not treated with antidepressants. There is only limited evidence on the association of antidepressant drug use with survival in glioblastoma. We performed a pooled analysis of patients treated within the CENTRIC, CORE, AVAglio and ACT‐IV trials to explore the relation of antidepressant drug use with progression‐free (PFS) and overall survival (OS) at baseline, at the start of maintenance therapy and at the start of maintenance cycle 4. We further assessed the association of antidepressant drugs with seizure, cognition, fatigue and a diagnosis of depression. Among more than 1700 patients, we found no significant association between the use of antidepressants at baseline or at the start of maintenance therapy and PFS or OS. However, we found OS, but not PFS, to be significantly worse in patients using antidepressants at the start of maintenance cycle 4. After adjustment for antiepileptic drug use and despite showing a trend for increased risk, seizures were not significantly associated with antidepressant drug use, nor was there a change in mini mental state examination (MMSE) scores or fatigue by antidepressant drug use at baseline. However, there was a significant positive association between antidepressant use at the start of maintenance treatment and fatigue during maintenance treatment. The association of antidepressant use at the start of maintenance cycle 4 with inferior OS of glioblastoma patients requires independent confirmation and further study. Further prospective trials should evaluate efficacy, side effects and associations with outcome of antidepressants in glioblastoma

Associations of levetiracetam use with the safety and tolerability profile of chemoradiotherapy for patients with newly diagnosed glioblastoma

Background Levetiracetam (LEV) is one of the most frequently used antiepileptic drugs (AED) for brain tumor patients with seizures. We hypothesized that toxicity of LEV and temozolomide-based chemoradiotherapy may overlap. Methods Using a pooled cohort of patients with newly diagnosed glioblastoma included in clinical trials prior to chemoradiotherapy (CENTRIC, CORE, AVAglio) or prior to maintenance therapy (ACT-IV), we tested associations of hematologic toxicity, nausea or emesis, fatigue, and psychiatric adverse events during concomitant and maintenance treatment with the use of LEV alone or with other AED versus other AED alone or in combination versus no AED use at the start of chemoradiotherapy and of maintenance treatment. Results Of 1681 and 2020 patients who started concomitant chemoradiotherapy and maintenance temozolomide, respectively, 473 and 714 patients (28.1% and 35.3%) were treated with a LEV-containing regimen, 538 and 475 patients (32.0% and 23.5%) with other AED, and 670 and 831 patients (39.9% and 41.1%) had no AED. LEV was associated with higher risk of psychiatric adverse events during concomitant treatment in univariable and multivariable analyses (RR 1.86 and 1.88, P < .001) while there were no associations with hematologic toxicity, nausea or emesis, or fatigue. LEV was associated with reduced risk of nausea or emesis during maintenance treatment in multivariable analysis (HR = 0.80, P = .017) while there were no associations with hematologic toxicity, fatigue, or psychiatric adverse events. Conclusions LEV is not associated with reduced tolerability of chemoradiotherapy in patients with glioblastoma regarding hematologic toxicity and fatigue. Antiemetic properties of LEV may be beneficial during maintenance temozolomide

Determinants of the varied profiles of Plasmodium falciparum infections among infants living in Kintampo, Ghana.

BACKGROUND: Understanding why some infants tolerate infections, remaining asymptomatic while others succumb to repeated symptomatic malaria is beneficial for studies of naturally acquired immunity and can guide control interventions. This study compared demographic, host and maternal factors associated with being either parasite negative or having asymptomatic infections versus developing symptomatic malaria in the first year of life. METHODS: A birth cohort (n = 1264) was monitored longitudinally over two years for malaria infections in Kintampo, Ghana. Symptomatic and asymptomatic infections were detected actively through monthly home visits, complemented by passive case detection. Light microscopy was used to detect parasitaemia. Based on data from a minimum of eight monthly visits within the first year of life, infants were classified into one of four groups: "parasite negative", "only-asymptomatic", "only-symptomatic" or "alternating" i.e., sometimes symptomatic and other times asymptomatic. The host and maternal characteristics and demographic factors in relation to these four groups were compared. RESULTS: The parasite negative group formed 36% of the cohort, whilst the only-symptomatic were 35%. The alternating group were 22% and the only-asymptomatic were 7% of the cohort. There were significant associations between residence, socio-economic status (SES), parity, IPTp doses, delivery place of infant and having or not having malaria parasites. Maternal factors such as early commencement and frequency of ante-natal care (ANC) were significantly higher in the parasite negative group compared to all others. ITN use in pregnancy increased the odds of infant having only asymptomatic infections ("protected against disease"). Placental malaria was more common in the groups of infants with symptomatic malaria. Urban residence was significantly higher in the parasite negative group, while birth in the malaria transmission season were significantly more common in the alternating and parasite negative groups. Risk factors for infants with symptomatic malaria included low SES, birth in private maternity homes, sickle cell normal variant, lower MUAC, reported intake of anti-malarials and increased morbidity before the first microscopic infection was detected. CONCLUSION: Strengthening ANC by encouraging early and regular attendance, the use of IPTp, maternal bed nets and improving the nourishment of infants help reduce the frequency of symptomatic malaria over the first year of life

Thrombocytopenia limits the feasibility of salvage lomustine chemotherapy in recurrent glioblastoma: a secondary analysis of EORTC 26101

BACKGROUND Thrombocytopenia represents the main cause of stopping alkylating chemotherapy for toxicity. Here, we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine in recurrent glioblastoma. METHODS We performed a retrospective analysis of the associations of thrombocytopenia with treatment delivery and outcome in EORTC 26101, a randomised trial designed to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma. RESULTS A total of 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients (57%) of group 1 and 187 patients (66%) of group 2 experiencing at least one episode of thrombocytopenia, 36 patients (16%) in group 1 and 93 (33%) in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. On adjusted analysis accounting for major prognostic factors, dose modification induced by thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumours in groups 1 and 2. This effect was noted for overall survival, too, but only for group 2 patients. CONCLUSION Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine chemotherapy in recurrent glioblastoma. Mitigating thrombocytopenia to enhance lomustine exposure might improve outcome in patients with MGMT promoter-methylated tumours

Intermittent preventive treatment of pregnant women in Kintampo area of Ghana with sulphadoxine-pyrimethamine (SP): trends spanning 2011 and 2015.

OBJECTIVE: In Ghana, intermittent preventive treatment during pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) is recommended for the prevention of malaria-related adverse outcomes. This study demonstrates the coverage of IPTp-SP use among pregnant women over a period (2011-2015) and the impact of various sociodemographic groups on the uptake of IPTp-SP. DESIGN: Retrospective analysis using data from all pregnant women in the Kintampo Health and Demographic Surveillance System area on the uptake of IPTp-SP. SETTING: Kintampo North Municipality and Kintampo South District of Ghana. PARTICIPANTS: All pregnant women in the Kintampo Health and Demographic Surveillance System area. PRIMARY AND SECONDARY OUTCOME MEASURES: The number of doses of IPTp-SP taken by pregnant women were examined. Logistic regression was used to assess the determinant of uptake of IPTp-SP while adjusting for within-subject correlation from women with multiple pregnancies. RESULTS: Data from 2011 to 2015 with a total of 17 484 pregnant women were used. The coverage of the recommended three or more doses of IPTp-SP among all pregnant women was 40.6%, 44.0%, 45.9%, 20.9% and 32.4% in 2011, 2012, 2013, 2014 and 2015, respectively. In the adjusted analysis, age, household size, education, religion, number of antenatal care visits, ethnicity, marital status, wealth index and place of residence were significantly associated with the uptake of three or more doses of IPTp-SP. Having middle school education or higher, aged 20 years and above, visiting antenatal care five times or more (OR 2.83, 95% CI 2.64 to 3.03), being married (OR 1.10, 95% CI 1.02 to 1.19) and those in higher wealth quintiles were significantly more likely to take three or more doses of IPTp-SP. CONCLUSION: The uptake of the recommended three or more doses of IPTp-SP is low in the study area. We recommend a community-based approach to identify women during early pregnancy and to administer IPTp-SP

Correction: Profiles of Plasmodium falciparum infections detected by microscopy through the first year of life in Kintampo a high transmission area of Ghana.

[This corrects the article DOI: 10.1371/journal.pone.0240814.]

Effectiveness of intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) in Ghana.

INTRODUCTION: Ghana adopted the revised WHO recommendation on intermittent preventive treatment in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) in 2012. This study has assessed the effectiveness and safety of this policy in Ghana. METHODS: A total of 1926 pregnant women enrolled at antenatal care (ANC) clinics were assessed for birth outcomes at delivery, and placental histology results for malaria infection were obtained from 1642 participants. Association of reduced placental or peripheral malaria, anaemia and low birth weight (LBW) in women who received ≥4 IPTp-SP doses compared with 3 or ≤2 doses was determined by logistic regression analysis. RESULTS: Among the 1926 participants, 5.3% (103), 19.2% (369), 33.2% (640) and 42.3% (817) of women had received ≤1, 2, 3 or ≥4 doses, respectively. There was no difference in risk of active placental malaria (PM) infection in women who received 3 doses compared with ≥4 doses (adjusted OR (aOR) 1.00, 95% CI 0.47 to 2.14). The risk of overall PM infection was 1.63 (95% CI 1.07 to 2.48) in 2 dose group and 1.06 (95% CI 0.72 to 1.57) in 3 dose group compared with ≥4 dose group. The risk of LBW was 1.55 (95% CI 0.97 to 2.47) and 1.06 (95% CI 0.68 to 1.65) for 2 and 3 dose groups, respectively, compared with the ≥4 dose group. Jaundice in babies was present in 0.16%, and 0% for women who received ≥4 doses of SP. CONCLUSION: There was no difference in the risk of PM, LBW or maternal anaemia among women receiving 3 doses compared with ≥4 doses. Receiving ≥3 IPTp-SP doses during pregnancy was associated with a lower risk of overall PM infection compared with 2 doses. As there are no safety concerns, monthly administration of IPTp-SP offers a more practical opportunity for pregnant women to receive ≥3 doses during pregnancy