Robert W. Makuch

Evidence that dyslexia may represent the lower tail of a normal distribution of reading ability.

BACKGROUND Dyslexia is now widely believed to be a biologically based disorder that is distinct from other, less specific reading problems. According to this view, reading ability is considered to follow a bimodal distribution, with dyslexia as the lower mode. We hypothesized that, instead, reading ability follows a normal distribution, with dyslexia at the lower end of the continuum. METHODS AND RESULTS We used data from the Connecticut Longitudinal Study, a sample survey of 414 Connecticut children who entered kindergarten in 1983 and were followed as a longitudinal cohort. Dyslexia was defined in terms of a discrepancy score, which represents the difference between actual reading achievement and achievement predicted on the basis of measures of intelligence. Data were available from intelligence tests administered in grades 1, 3, and 5 and achievement tests administered yearly in grades 1 through 6. For each child there were 108 possible discrepancy scores ([3 x 3 years] x [2 x 6 years]) based on combinations of the ability scores (full-scale, verbal, and performance IQ) in each of three years and two achievement scores (reading and mathematics) in each of six years. We demonstrated that each of the discrepancy scores followed a univariate normal distribution and that the interrelation of two different discrepancy scores followed a bivariate normal distribution. At most, only 9 of 108 discrepancy scores (8.3 percent) and 171 of 3402 pairs of discrepancy scores (5.0 percent) were significantly different (at the 5 percent level) from the expected scores--well within the expected values for data with univariate and bivariate normal distributions, respectively. We also examined the stability of dyslexia over time. The normal-distribution model predicted (and the data indicated) that only 7 of the 25 children (28 percent) classified as having dyslexia in grade 1 would also be classified as having dyslexia in grade 3. CONCLUSIONS Reading difficulties, including dyslexia, occur as part of a continuum that also includes normal reading ability. Dyslexia is not an all-or-none phenomenon, but like hypertension, occurs in degrees. The variability inherent in the diagnosis of dyslexia can be both quantified and predicted with use of the normal-distribution model.

Stratified randomization for clinical trials.

Trialists argue about the usefulness of stratified randomization. For investigators designing trials and readers who use them, the argument has created uncertainty regarding the importance of stratification. In this paper, we review stratified randomization to summarize its purpose, indications, accomplishments, and alternatives. In order to identify research papers, we performed a Medline search for 1966-1997. The search yielded 33 articles that included original research on stratification or included stratification as the major focus. Additional resources included textbooks. Stratified randomization prevents imbalance between treatment groups for known factors that influence prognosis or treatment responsiveness. As a result, stratification may prevent type I error and improve power for small trials (<400 patients), but only when the stratification factors have a large effect on prognosis. Stratification has an important effect on sample size for active control equivalence trials, but not for superiority trials. Theoretical benefits include facilitation of subgroup analysis and interim analysis. The maximum desirable number of strata is unknown, but experts argue for keeping it small. Stratified randomization is important only for small trials in which treatment outcome may be affected by known clinical factors that have a large effect on prognosis, large trials when interim analyses are planned with small numbers of patients, and trials designed to show the equivalence of two therapies. Once the decision to stratify is made, investigators need to chose factors carefully and account for them in the analysis.

Histopathologic staging at initial diagnosis of mycosis fungoides and the Sézary syndrome. Definition of three distinctive prognostic groups.

STUDY OBJECTIVE To determine the optimal staging evaluation at the time of initial diagnosis of mycosis fungoides or the Sézary syndrome. DESIGN Retrospective review of a uniformly staged inception cohort. SETTING Single-institution tertiary care center. PATIENTS 152 consecutive patients who had mycosis fungoides with or without the Sézary syndrome within 6 months of the initial definitive diagnosis. INTERVENTION A detailed staging evaluation including physical examination, routine laboratory studies, chest roentgenogram, lymphangiogram, peripheral blood smear, lymph node biopsy, bone marrow aspirate or biopsy, and liver biopsy in selected patients. MEASUREMENTS AND MAIN RESULTS Univariate adverse prognostic features at initial diagnosis in patients with mycosis fungoides included (P less than 0.01) one or more cutaneous tumors or generalized erythroderma, adenopathy, blood smear involvement with Sézary cells, lymph node effacement, eosinophilia, and visceral involvement. Important, independent prognostic factors in a multivariate analysis are the presence of visceral disease and type of skin involvement. CONCLUSIONS A staging system based on histopathologic evaluation of skin, lymph nodes, blood, and visceral sites provides more comprehensive prognostic information than clinical evaluation of skin disease and adenopathy. Patients may be divided at initial presentation into three prognostic groups: good-risk patients, who have plaque-only skin disease without lymph node, blood, or visceral involvement (median survival, greater than 12 years); intermediate-risk patients, who have cutaneous tumors, erythroderma, or plaque disease with node or blood involvement but no visceral disease or node effacement (median survival, 5 years); and poor-risk patients, who have visceral involvement or node effacement (median survival, 2.5 years).

Variations in the natural history and survival of patients with supratentorial low-grade astrocytomas.

Data from 55 consecutive patients with low-grade astrocytomas treated between 1982 and 1990 were analyzed to determine specific outcome factors, including time to recurrence, incidence of anaplastic transformation, and survival. Gender, type of symptoms, contrast enhancement, and timing of radiation therapy were not significant in determining outcome. Patients who had symptoms for > 2 years and underwent gross-total resection of the tumor, with age as a continuous variable, were associated with significantly longer time to recurrence and survival. Within the population of patients with low-grade astrocytomas, patients with chronic epilepsy clearly had the best prognoses. There were no tumor recurrences or deaths in 27 patients with chronic epilepsy, regardless of the extent of surgery and without the use of radiotherapy. Ten-year survival was 100% for 31 patients who underwent gross-total tumor resection, regardless of the length of preoperative symptoms. Immediate postoperative radiotherapy did not prolong the time to recurrence, reduce the incidence of transition to more malignant tumors at recurrence, or increase the length of survival when compared with delayed radiotherapy. Because recurrence with a high-grade lesion caused 92% of the mortality in our series, the benefit in patients who underwent aggressive surgery seems to result from a significant decrease in the risk of recurrence when compared with patients who underwent anything less than gross-total resection. Our data also suggest that variability in the natural history of low-grade astrocytomas has a strong influence in determining survival and that tumors associated with chronic epilepsy are much less likely to become more malignant over time.

Prematurely Born Children Demonstrate White Matter Microstructural Differences at 12 Years of Age, Relative to Term Control Subjects : An Investigation of Group and Gender Effects

OBJECTIVE. The goal was to use diffusion tensor imaging to test the hypothesis that prematurely born children demonstrate long-term, white matter, microstructural differences, relative to term control subjects. METHODS. Twenty-nine preterm subjects (birth weight: 600–1250 g) without neonatal brain injury and 22 matched, term, control subjects were evaluated at 12 years of age with MRI studies, including diffusion tensor imaging and volumetric imaging; voxel-based morphometric strategies were used to corroborate regional diffusion tensor imaging results. Subjects also underwent neurodevelopmental assessments. RESULTS. Neurodevelopmental assessments showed significant differences in full-scale, verbal, and performance IQ and Developmental Test of Visual Motor Integration scores between the preterm and term control subjects. Diffusion tensor imaging studies demonstrated widespread decreases in fractional anisotropy (a measure of fiber tract organization) in the preterm children, compared with the control subjects. Regions included both intrahemispheric association fibers subserving language skills, namely, the right inferior frontooccipital fasciculus and anterior portions of the uncinate fasciculi bilaterally, and the deep white matter regions to which they project, as well as the splenium of the corpus callosum. These changes in fractional anisotropy occurred in subjects with significant differences in frontal, temporal, parietal, and deep white matter volumes. Fractional anisotropy values in the left anterior uncinate correlated with verbal IQ, full-scale IQ, and Peabody Picture Vocabulary Test-Revised scores for preterm male subjects. In addition, preterm male subjects were found to have the lowest values for fractional anisotropy in the right anterior uncinate fasciculus, and fractional anisotropy values in that region correlated with both verbal IQ and Peabody Picture Vocabulary Test-Revised scores for the preterm groups; these findings were supported by changes identified with voxel-based morphometric analyses. CONCLUSIONS. Compared with term control subjects, prematurely born children with no neonatal ultrasound evidence of white matter injury manifest changes in neural connectivity at 12 years of age.

Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis

BACKGROUND/AIMS A total of 213 patients with compensated cirrhosis, portal hypertension and no varices were included in a trial evaluating beta-blockers in preventing varices. Predictors of the development of hepatocellular carcinoma (HCC), including hepatic venous pressure gradient (HVPG) were analyzed. METHODS Baseline laboratory tests, ultrasound and HVPG measurements were performed. Patients were followed prospectively every three months until development of varices or variceal bleeding or end of the study in 09/02. The endpoint was HCC development according to standard diagnostic criteria. Univariate and multivariate Cox regression models were developed to identify predictors of HCC. RESULTS In a median follow-up of 58 months 26/213 (12.2%) patients developed HCC. Eight patients were transplanted and 28 patients died without HCC. Twenty-one (84%) HCC developed in patients with HCV. On multivariate analysis HVPG (HR 1.18; 95%CI 1.08-1.29), albumin (HR 0.34; 95%CI 0.14-0.83) and viral etiology (HR 4.59; 95%CI 1.51-13.92) were independent predictors of HCC development. ROC curves identified 10 mmHg of HVPG as the best cut-off; those who had an HVPG above this value had a 6-fold increase in the HCC incidence. CONCLUSIONS Portal hypertension is an independent predictor of HCC development. An HVPG >10 mmHg is associated with a 6-fold increase of HCC risk.

The clinical behavior of 'mixed' small cell/large cell bronchogenic carcinoma compared to 'pure' small cell subtypes

Biopsy specimens from 19 previously untreated lung cancer patients were prospectively diagnosed as small cell carcinoma with a large cell component. The patients were thoroughly staged and received intensive combination chemotherapy. They represented 12% of all small cell carcinoma cases eligible for aggressive chemotherapy protocols during a 5.5 year period. To determine whether the clinical behavior of this ‘mixed’ histologic variant differed from the other histologic subtypes of small cell lung cancer, we compared these 19 patients to a concurrent group of 103 patients with only small cell cancer in their diagnostic biopsies given equivalent therapy. The ‘mixed’ histology patients were comparable to the ‘pure’ small cell group in age, performance status, extent of disease, and frequency of bone marrow, liver, bone, and central nervous system metastases. Their complete plus partial response rate (58%) was significantly less than the response rate for the ‘pure’ small cell patients (91%), their complete response rate was also lower (16 versus 46%), and their overall survival was significantly shorter (median, 6 versus 10.5 months). Mixed histology small cell/large cell carcinoma represents a distinct pathologic variant of small cell carcinoma of the lung, associated with lower response rates and shorter survival than the ‘pure’ small cell subtypes. Since combination chemotherapy yields some complete responses and long‐term disease‐free survival in these patients, however, aggressive treatment with potentially curative intent should be considered in their management.

Antenatal steroids, delivery mode, and intraventricular hemorrhage in preterm infants

OBJECTIVE The relationship between antenatal steroids, delivery mode, and early-onset intraventricular hemorrhage was examined in very-low-birth-weight infants. STUDY DESIGN A total of 505 preterm infants (birth weight 600 to 1250 gm) were enrolled in a multicenter, prospectively randomized, controlled trial evaluating the efficacy of postnatal indomethacin to prevent intraventricular hemorrhage. All infants had echoencephalography between 5 and 11 hours of life. RESULTS Seventy-three infants had intraventricular hemorrhage within the first 5 to 11 hours (mean age at echoencephalography 7.5 hours). Four hundred thirty-two infants did not have early intraventricular hemorrhage. There was less antenatal steroid treatment (19% vs 32%, p = 0.03) and more vaginal deliveries (71% vs 45%, p < 0.0001) in the group with early intraventricular hemorrhage. Of 152 infants who received antenatal steroids, those delivered by cesarean section had significantly less early-onset intraventricular hemorrhage than did those delivered vaginally (4% vs 17%, p = 0.02). Of the 353 not exposed to antenatal steroids, 10% of infants delivered by cesarean section and 22% delivered vaginally had early intraventricular hemorrhage (p = 0.003). CONCLUSION These data are the first to suggest that both antenatal steroids and cesarean section delivery have an important and independent role in lowering the risk of early-onset intraventricular hemorrhage.

Brain Volume Reductions within Multiple Cognitive Systems in Male Preterm Children at Age Twelve

OBJECTIVES To more precisely examine regional and subregional microstructural brain changes associated with preterm birth. STUDY DESIGN We obtained brain volumes from 29 preterm children, age 12 years, with no ultrasound scanning evidence of intraventricular hemorrhage or cystic periventricular leukomalacia in the newborn period, and 22 age- and sex-matched term control subjects. RESULTS Preterm male subjects demonstrated significantly lower white matter volumes in bilateral cingulum, corpus callosum, corticospinal tract, prefrontal cortex, superior and inferior longitudinal fasciculi compared with term male subjects. Gray matter volumes in prefrontal cortex, basal ganglia, and temporal lobe also were significantly reduced in preterm male subjects. Brain volumes of preterm female subjects were not significantly different from those of term female control subjects. Voxel-based morphometry results were not correlated with perinatal variables or cognitive outcome. Higher maternal education was associated with higher cognitive performance in preterm male subjects. CONCLUSIONS Preterm male children continue to demonstrate abnormal neurodevelopment at 12 years of age. However, brain morphology in preterm female children may no longer differ from that of term female children. The neurodevelopmental abnormalities we detected in preterm male subjects appear to be relatively diffuse, involving multiple neural systems. The relationship between aberrant neurodevelopment and perinatal variables may be mediated by genetic factors, environmental factors, or both reflected in maternal education level.

The Stroke Prognosis Instrument II (SPI-II) A Clinical Prediction Instrument for Patients With Transient Ischemia and Nondisabling Ischemic Stroke

BACKGROUND AND PURPOSE In 1991 we developed the Stroke Prognosis Instrument (SPI-I) to stratify patients with transient ischemic attack or ischemic stroke by prognosis for stroke or death in 2 years. In this article we validate and improve SPI-I (creating SPI-II). METHODS To validate SPI-I, we applied it to 4 test cohorts and calculated pooled outcome rates. To create SPI-II, we incorporated new predictive variables identified in 1 of the test cohorts and validated it in the other 3 cohorts. RESULTS For SPI-I, pooled rates (all 4 test cohorts) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 24%, respectively (P<0.01, log-rank test). SPI-II was created by adding congestive heart failure and prior stroke to SPI-I. Each patients risk group was determined by the total score for 7 factors: congestive heart failure (3 points); diabetes (3 points); prior stroke (3 points); age >70 years (2 points); stroke for the index event (not transient ischemic attack) (2 points); hypertension (1 point); and coronary artery disease (1 point). Risk groups I, II, and III comprised patients with 0 to 3, 4 to 7, and 8 to 15 points, respectively. For SPI-I, pooled rates (3 cohorts excluding the SPI-II development cohort) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 23%, respectively. For SPI-II, pooled rates were 10%, 19%, and 31%, respectively. In receiver operator characteristic analysis, the area under the curve was 0.59 (95% CI, 0.57 to 0.60) for SPI-I and 0.63 (95% CI, 0.62 to 0.65) for SPI-II, confirming the better performance of the latter. CONCLUSIONS Compared with SPI-I, SPI-II achieves greater discrimination in outcome rates among risk groups. SPI-II is ready for use in research design and may have a role in patient counseling.