Multiple imputation for missing continuous and dichotomous data: The effects of patterns of missingness and variable correlations on type I error with small samples

The purpose of this study is to investigate the effects of predictor variable correlations and patterns of missingness with dichotomous and/or continuous data in small samples when missing data is multiply imputed. Missing data of predictor variables is multiply imputed under three different multivariate models: the multivariate normal model for continuous data, the multinomial model for dichotomous data and the general location model for mixed dichotomous and continuous data. Subsequent to the multiple imputation process, Type I error rates of the regression coefficients obtained with logistic regression analysis are estimated under various conditions of correlation structure, sample size, type of data and patterns of missing data. The distributional properties of average mean, variance and correlations among the predictor variables are assessed after the multiple imputation process. ^ For continuous predictor data under the multivariate normal model, Type I error rates are generally within the nominal values with samples of size n = 100. Smaller samples of size n = 50 resulted in more conservative estimates (i.e., lower than the nominal value). Correlation and variance estimates of the original data are retained after multiple imputation with less than 50% missing continuous predictor data. For dichotomous predictor data under the multinomial model, Type I error rates are generally conservative, which in part is due to the sparseness of the data. The correlation structure for the predictor variables is not well retained on multiply-imputed data from small samples with more than 50% missing data with this model. For mixed continuous and dichotomous predictor data, the results are similar to those found under the multivariate normal model for continuous data and under the multinomial model for dichotomous data. With all data types, a fully-observed variable included with variables subject to missingness in the multiple imputation process and subsequent statistical analysis provided liberal (larger than nominal values) Type I error rates under a specific pattern of missing data. It is suggested that future studies focus on the effects of multiple imputation in multivariate settings with more realistic data characteristics and a variety of multivariate analyses, assessing both Type I error and power. ^

Treatment of a Class II subdivision malocclusion with multiple congenitally missing teeth

This case report describes the treatment of a patient with a Class II Division 1 subdivision right malocclusion with 8 congenitally missing teeth, incompetent lips, and incisor protrusion. The treatment plan included extractions and space closure with retraction of the anterior teeth; symmetric mechanics were used in the mandibular arch and asymmetric mechanics in the maxillary arch. Because of the mechanics used, some midline deviations were expected. Knowledge of diagnosis and treatment planning of asymmetric malocclusions and dental esthetics are essential for success when correcting asymmetic problems, but, even so, small clinical compromises should be expected. (Am J Orthod Dentofacial Orthop 2009; 135: 663-70)

Multiple imputation of missing blood alcohol concentration (BAC) values in FARS.

National Highway Traffic Safety Administration, Washington, D.C.

Neutron Activation Analysis: A Primary (Ratio) Method to Determine SI-Traceable Values of Element Content in Complex Samples

The metrological principles of neutron activation analysis are discussed. It has been demonstrated that this method can provide elemental amount of substance with values fully traceable to the SI. The method has been used by several laboratories worldwide in a number of CCQM key comparisons - interlaboratory comparison tests at the highest metrological level - supplying results equivalent to values from other methods for elemental or isotopic analysis in complex samples without the need to perform chemical destruction and dissolution of these samples. The CCOM accepted therefore in April 2007 the claim that neutron activation analysis should have the similar status as the methods originally listed by the CCOM as `primary methods of measurement`. Analytical characteristics and scope of application are given.

Antiretroviral treatment for HIV infection/AIDS and the risk of developing hyperglycemia and hyperlipidemia

A cross-sectional study with internal comparison groups was conducted to describe sociodemographic characteristics, as well as verify the association between the type of antiretroviral treatment used and hyperglycemia and hyperlipidemia, with special attention to the use of HIV protease inhibitors. The data was obtained through an interview questionnaire, as well as blood and urine samples that were collected for the laboratory exams. A total of 418 patients were interviewed. 46 of these, however, met the exclusion criteria. The sample was therefore composed by 372 HIV positive patients, attended at the laboratory of the Correia Picanço State Hospital for the collection of blood, to estimate the HIV viral load and/or TCD4 cell counts from August to November 2000. The association between the variables was tested using the chi-square test and the p-value. A multiple logistic regression analysis was carried out to adjust for potential confounding factors. A greater frequency of patients with high glucose levels was observed among those making use of antiretroviral therapy without protease inhibitors, but the number of patients limited the comparisons. An association was verified between the total serum cholesterol level and the use of HIV protease inhibitors (p = 0.047) even after controlling for age. An association was also observed between the triglyceride levels and the use of HIV protease inhibitors, which remained after adjustment for age, sex and creatinine levels (p < 0.001). The levels of glucose and TSH, the presence of proteinuria and the practice of physical activity were not associated either with the levels of cholesterol or with the levels of tryglicerides thus they were not confounders of the associations described.

Adherence to interferon β-1b treatment in patients with multiple sclerosis in Spain

BACKGROUND Adherence to interferon β-1b (INFβ-1b) therapy is essential to maximize the beneficial effects of treatment in multiple sclerosis (MS). For that reason, the main objectives of this study are to assess adherence to INFβ-1b in patients suffering from MS in Spain, and to identify the factors responsible for adherence in routine clinical practice. METHODOLOGY/PRINCIPAL FINDINGS This was an observational, retrospective, cross-sectional study including 120 Spanish patients with MS under INFβ-1b treatment. Therapeutic adherence was assessed with Morisky-Green test and with the percentage of doses received. The proportion of adherent patients assessed by Morisky-Green test was 68.3%, being indicative of poor adherence. Nevertheless, the percentage of doses received, which was based on the number of injected medication, was 94.3%. The main reason for missing INFβ-1b injections was forgetting some of the administrations (64%). Therefore, interventions that diminish forgetfulness might have a positive effect in the proportion of adherent patients and in the percentage of doses received. In addition, age and comorbidities had a significant effect in the number of doses injected per month, and should be considered in the management of adherence in MS patients. CONCLUSION/SIGNIFICANCE Among all the available methods for assessing adherence, the overall consumption of the intended dose has to be considered when addressing adherence.

Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study.

BACKGROUND: Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy (PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment. METHODS: We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay. The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment. FINDINGS: We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta. INTERPRETATION: Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation. FUNDING: Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.

Measurement of Bioactivity of Immunomodulatory Treatment of Relapsing Multiple Sclerosis. With Emphasis on MxA Protein

Background Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, which mainly affects young adults. In Finland, approximately 2500 out of 6000 MS patients have relapsing MS and are treated with disease modifying drugs (DMD): interferon- β (INF-β-1a or INF-β-1b) and glatiramer acetate (GA). Depending on the used IFN-β preparation, 2 % to 40 % of patients develop neutralizing antibodies (NAbs), which abolish the biological effects of IFN-β, leading to reduced clinical and MRI detected efficacy. According to the Finnish Current Care Guidelines and European Federation of Neurological Societis (EFNS) guidelines, it is suggested tomeasure the presence of NAbs during the first 24 months of IFN-β therapy. Aims The aim of this thesis was to measure the bioactivity of IFN-β therapy by focusing on the induction of MxA protein (myxovirus resistance protein A) and its correlation to neutralizing antibodies (NAb). A new MxA EIA assay was set up to offer an easier and rapid method for MxA protein detection in clinical practice. In addition, the tolerability and safety of GA were evaluated in patients who haddiscontinued IFN-β therapy due to side effects and lack of efficacy. Results NAbs developed towards the end of 12 months of treatment, and binding antibodies were detectable before or parallel with them. The titer of NAb correlated negatively with the amount of MxA protein and the mean values of preinjection MxA levels never returned to true baseline in NAb negative patients, but tended to drop in the NAb positive group. The test results between MxA EIA and flow cytometric analysis showed significant correlation. GA reduced the relapse rate and was a safe and well-tolerated therapy in IFN-β-intolerant MS patients. Conclusions NAbs inhibit the induction of MxA protein, which can be used as a surrogate marker of the bioactivity of IFN-β therapy. Compared to flow cytometricanalysis and NAb assay, MxA-EIA seemed to be a sensitive and more practical method in clinical use to measure the actual bioactivity of IFN-β treatment, which is of value also from a cost-effective perspective.

Critical points in logistic growth curves and treatment comparisons

Several biological phenomena have a behavior over time mathematically characterized by a strong increasing function in the early stages of development, then by a less pronounced growth, sometimes showing stability. The separation between these phases is very important to the researcher, since the maintenance of a less productive phase results in uneconomical activity. In this report we present methods of determining critical points in logistic functions that separate the early stages of growth from the asymptotic phase, with the aim of establishing a stopping critical point in the growth and on this basis determine differences in treatments. The logistic growth model is fitted to experimental data of imbibition of arariba seeds (Centrolobium tomentosum). To determine stopping critical points the following methods were used: i) accelerating growth function, ii) tangent at the inflection point, iii) segmented regression; iv) modified segmented regression; v) non-significant difference; and vi) non-significant difference by simulation. The analysis of variance of the abscissas and ordinates of the breakpoints was performed with the objective of comparing treatments and methods used to determine the critical points. The methods of segmented regression and of the tangent at the inflection point lead to early stopping points, in comparison with other methods, with proportions ordinate/asymptote lower than 0.90. The non-significant difference method by simulation had higher values of abscissas for stopping point, with an average proportion ordinate/asymptote equal to 0.986. An intermediate proportion of 0.908 was observed for the acceleration function method.

Drug hypersensitivity: flare-up reactions, cross-reactivity and multiple drug hypersensitivity

In drug hypersensitivity, change of drug treatment and continuation with a new drug may result in reappearance of drug hypersensitivity symptoms. This is not uncommon in patients with chronic infections requiring continued and long-lasting antibiotic treatments. For the clinician, the question arises whether these symptoms are due to cross-reactivity, are due to a new sensitization or are a reflection of a multiple drug hypersensitivity syndrome. Based on the p-i concept (pharmacological interaction with immune receptors), we propose that the efficient stimulation of T cells by a drug is the sum of drug-T-cell receptor affinity and readiness of the T cell to react, and therefore not constant. It heavily depends on the state of underlying immune activation. Consequently, drug hypersensitivity diseases, which go along with massive immune stimulations and often high serum cytokine values, are themselves risk factors for further drug hypersensitivity. The immune stimulation during drug hypersensitivity may, similar to generalized virus infections, lower the threshold of T-cell reactivity to drugs and cause rapid appearance of drug hypersensitivity symptoms to the second drug. We call the second hypersensitivity reaction a "flare-up" reaction; this is clinically important, as in most cases the second drug may be tolerated again, if the cofactors are missing. Moreover, the second treatment is often too short to cause a relevant sensitization.

Treatment of multiple adjacent Miller class I and II gingival recessions with a Modified Coronally Advanced Tunnel (MCAT) technique and a collagen matrix or palatal connective tissue graft: a randomized, controlled clinical trial

BACKGROUND A newly developed collagen matrix (CM) of porcine origin has been shown to represent a potential alternative to palatal connective tissue grafts (CTG) for the treatment of single Miller Class I and II gingival recessions when used in conjunction with a coronally advanced flap (CAF). However, at present it remains unknown to what extent CM may represent a valuable alternative to CTG in the treatment of Miller Class I and II multiple adjacent gingival recessions (MAGR). The aim of this study was to compare the clinical outcomes following treatment of Miller Class I and II MAGR using the modified coronally advanced tunnel technique (MCAT) in conjunction with either CM or CTG. METHODS Twenty-two patients with a total of 156 Miller Class I and II gingival recessions were included in this study. Recessions were randomly treated according to a split-mouth design by means of MCAT + CM (test) or MCAT + CTG (control). The following measurements were recorded at baseline (i.e. prior to surgery) and at 12 months: Gingival Recession Depth (GRD), Probing Pocket Depth (PD), Clinical Attachment Level (CAL), Keratinized Tissue Width (KTW), Gingival Recession Width (GRW) and Gingival Thickness (GT). GT was measured 3-mm apical to the gingival margin. Patient acceptance was recorded using a Visual Analogue Scale (VAS). The primary outcome variable was Complete Root Coverage (CRC), secondary outcomes were Mean Root Coverage (MRC), change in KTW, GT, patient acceptance and duration of surgery. RESULTS Healing was uneventful in both groups. No adverse reactions at any of the sites were observed. At 12 months, both treatments resulted in statistically significant improvements of CRC, MRC, KTW and GT compared with baseline (p < 0.05). CRC was found at 42% of test sites and at 85% of control sites respectively (p < 0.05). MRC measured 71 ± 21% mm at test sites versus 90 ± 18% mm at control sites (p < 0.05). Mean KTW measured 2.4 ± 0.7 mm at test sites versus 2.7 ± 0.8 mm at control sites (p > 0.05). At test sites, GT values changed from 0.8 ± 0.2 to 1.0 ± 0.3 mm, and at control sites from 0.8 ± 0.3 to 1.3 ± 0.4 mm (p < 0.05). Duration of surgery and patient morbidity was statistically significantly lower in the test compared with the control group respectively (p < 0.05). CONCLUSIONS The present findings indicate that the use of CM may represent an alternative to CTG by reducing surgical time and patient morbidity, but yielded lower CRC than CTG in the treatment of Miller Class I and II MAGR when used in conjunction with MCAT.