Rethinking PICO in the Machine Learning Era: ML-PICO

Background  Machine learning (ML) has captured the attention of many clinicians who may not have formal training in this area but are otherwise increasingly exposed to ML literature that may be relevant to their clinical specialties. ML papers that follow an outcomes-based research format can be assessed using clinical research appraisal frameworks such as PICO (Population, Intervention, Comparison, Outcome). However, the PICO frameworks strain when applied to ML papers that create new ML models, which are akin to diagnostic tests. There is a need for a new framework to help assess such papers. Objective  We propose a new framework to help clinicians systematically read and evaluate medical ML papers whose aim is to create a new ML model: ML-PICO (Machine Learning, Population, Identification, Crosscheck, Outcomes). We describe how the ML-PICO framework can be applied toward appraising literature describing ML models for health care. Conclusion  The relevance of ML to practitioners of clinical medicine is steadily increasing with a growing body of literature. Therefore, it is increasingly important for clinicians to be familiar with how to assess and best utilize these tools. In this paper we have described a practical framework on how to read ML papers that create a new ML model (or diagnostic test): ML-PICO. We hope that this can be used by clinicians to better evaluate the quality and utility of ML papers.     

Comparison of energy expenditure estimated in healthy infants using the doubly labelled water and energy balance methods

The doubly labelled water method was used to estimate energy expenditure in 20 formula-fed infants (10 aged 1 month and 10 aged 4 months). We then compared the energy expenditure values with energy balance values calculated from energy intake and energy cost of growth. Our purpose was to compare various published equations for calculating CO2 expiration rates (and thus energy expenditure values) from the isotopic data. Those equations in which we used measured values for 18O and 2H isotope dilution spaces and estimated or measured values for insensible water losses yielded energy expenditure values (69.7 +/- 8.4 kcal/kg/d) that agreed most closely with energy balance data (70.3 +/- 11.9 kcal/kg/d). Equations in which we used a constant ratio of 1.03 between the 2H and 18O isotope dilution spaces resulted in energy expenditure values (66.3 +/- 10.2 kcal/kg/d) lower than those predicted by the energy balance data. Data analysis by nonlinear curve fitting compared to logarithmic transformation did not alter the estimates of energy expenditure obtained in these infants.     

Insulin signal transduction pathways.

Insulin initiates its pleiotropic effects by activating the insulin receptor tyrosine kinase to phosphorylate several intracellular proteins. Recent studies have demonstrated that phosphotyrosine residues bind specifically to proteins that contain src homology 2 (SH2) domains, and that this interaction mediates the regulation of multiple intracellular signaling pathways. This article reviews recent progress in elucidating the detailed pathways that lead from the insulin receptor to the ultimate biologic actions of insulin.     

Solitary bronchioloalveolar carcinoma: CT criteria

The computed tomographic (CT) scans of 30 patients with solitary bronchioloalveolar carcinoma were reviewed. Common features at CT included the peripheral or subpleural location of a pulmonary mass (25 cases), pseudocavitation (18 cases), heterogeneous attenuation (17 cases), irregular margins forming a star pattern (22 cases), and pleural tags (21 cases). Using these CT criteria, four independent observers attempted to identify cases of bronchioloalveolar carcinoma from a larger sample of lung cancers and benign lesions by categorizing a series of test cases into four probability categories. Although the bronchioloalveolar carcinomas were correctly ranked in the two highest probability categories 75% of the time (in 45 of 60 cases), there was considerable overlap with other lung lesions, particularly with adenocarcinoma and large cell undifferentiated carcinoma. However, even though the typical features of bronchioloalveolar carcinoma are not invariable or highly specific, they are characteristic enough to suggest the diagnosis.     

Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair

The association between MSHR coding region variation and hair colour in humans has been examined by genotyping 25 red haired and 62 non-red Caucasians, all of whom were 12 years of age and members of a twin pair study. Twelve amino acid substitutions were seen at 11 different sites, nine of these being newly described MSHR variants. The previously reported Val92Met allele shows no association with hair colour, but the three alleles Arg151Cys, Arg160Trp and Asp294His were associated with red hair and one Val60Leu variant was most frequent in fair/blonde and light brown hair colours. Variant MSHR genotypes are associated with lighter skin types and red hair (P < 0.001). However, comparison of the MSHR genotypes in dizygotic twin pairs discordant for red hair colour indicates that the MSHR gene cannot be solely responsible for the red hair phenotype, since five of 13 pairs tested had both haplotypes identical by state (with three of the five having both identical by descent). Rather, it is likely that additional modifier genes exist, making variance in the MSHR gene necessary but not always sufficient, for red hair production.      

Lactation delays postpartum bone mineral accretion and temporarily alters its regional distribution in women

The objective of this work was to compare long-term changes in bone mineral in lactating (L) and nonlactating (NL) women for 2 y postpartum. The 40 L women (mean duration of breastfeeding 345 +/- 177 d) and 36 NL women were enrolled during late pregnancy. Subjects were healthy and nonsmoking with a mean age of 28.8 +/- 4.1 y. Bone mineral content (BMC) was measured at 0.5, 3, 6, 12, 18 and 24 mo by dual-energy X-ray absorptiometry set for total body scan with regional analysis. BMC adjusted for bone area, weight and height (adj-BMC) decreased in L women at the lumbar spine (-3.1%, P < 0. 001) and pelvis (-0.9%, P = 0.03) by 3 mo, and at the total body (-0. 9%, P = 0.05) by 6 mo. Losses were recovered following onset of menses. Adj-BMC at the lumbar spine, pelvis, thoracic spine and total body increased over baseline by 24 mo in L women. In NL women, adj-BMC increased over baseline within 3 mo and continued to increase thereafter. Net total-body gains were greater in the 27 NL women who completed the final measurement than in their 26 L counterparts (+2.3% vs. +0.6%, P = 0.001). Net regional gains differed at the head, legs, and ribs, but not at the lumber spine, pelvis or thoracic spine. Duration of breastfeeding, parity, onset of menses and maternal age affected bone changes in L women. These results indicate that lactation delays bone mineral accretion and temporarily alters its regional distribution in postpartum women.     

Genetic and environmental factors influencing fasting serum adiponectin in Hispanic children

CONTEXT: Because of its antiinflammatory and insulin-sensitizing properties, adiponectin may play a role in the development of cardiovascular disease and type 2 diabetes. OBJECTIVES: The aims of these analyses were: 1) to estimate the heritability of fasting serum adiponectin; 2) to evaluate the effects of age, sex, and body composition on fasting serum adiponectin; 3) to test for associations between fasting serum adiponectin and diet, fitness, energy expenditure, and fat oxidation; and 4) to determine the relationships between fasting serum adiponectin, insulin and lipids, and blood pressure in Hispanic children. DESIGN: Genetic and environmental factors influencing fasting serum adiponectin were investigated in a cohort of children participating in the VIVA LA FAMILIA Study in 2000-2005. SETTING: This study was performed at the Children's Nutrition Research Center. PARTICIPANTS: The study participants were 805 Hispanic nonoverweight and overweight children, ages 4-19 yr. MAIN MEASURE: The main measure of the study was fasting serum adiponectin. RESULTS: The heritability of serum adiponectin was 0.93 +/- 0.10 (P = 2.4 x 10(-40)). Adiponectin differed by age (P = 0.001), sex (P = 0.04), and weight (P = 0.001) status. Adiponectin levels declined with age, in association with changes in sex hormones and growth factors. Adiponectin was not associated with macronutrient intake, fitness, 24-h energy expenditure, or fat oxidation. Controlling for age, sex, and percent fat mass, adiponectin was inversely associated with homeostasis model of insulin resistance, triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure (P = 0.001). Significant positive genetic correlations were detected between adiponectin and total cholesterol (rho(G) = 0.19), HDL-C (rho(G) = 0.32), low-density lipoprotein cholesterol (rho(G) = 0.24), and IGF-binding protein-1 (rho(G) = 0.39), and negative genetic correlations were detected between adiponectin and leptin (rho(G) = -0.30), TG (rho(G) = -0.21), TG/HDL-C (rho(G) = -0.33), and IGF-binding protein-3 (rho(G) = -0.32), indicating shared genetic components in their expression. CONCLUSION: The high heritability of adiponectin and pleiotropy seen between adiponectin and leptin, growth factors, and lipids may play a role in the pathogenesis of cardiovascular disease and type 2 diabetes in overweight Hispanic children.     

The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function post myocardial infarction

Regeneration of the damaged myocardium is one of the most challenging fronts in the field of tissue engineering due to the limited capacity of adult heart tissue to heal and to the mechanical and structural constraints of the cardiac tissue. In this study we demonstrate that an engineered acellular scaffold comprising type I collagen, endowed with specific physiomechanical properties, improves cardiac function when used as a cardiac patch following myocardial infarction. Patches were grafted onto the infarcted myocardium in adult murine hearts immediately after ligation of left anterior descending artery and the physiological outcomes were monitored by echocardiography, and by hemodynamic and histological analyses four weeks post infarction. In comparison to infarcted hearts with no treatment, hearts bearing patches preserved contractility and significantly protected the cardiac tissue from injury at the anatomical and functional levels. This improvement was accompanied by attenuated left ventricular remodeling, diminished fibrosis, and formation of a network of interconnected blood vessels within the infarct. Histological and immunostaining confirmed integration of the patch with native cardiac cells including fibroblasts, smooth muscle cells, epicardial cells, and immature cardiomyocytes. In summary, an acellular biomaterial with specific biomechanical properties promotes the endogenous capacity of the infarcted myocardium to attenuate remodeling and improve heart function following myocardial infarction.     

Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia [see comments]

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.