Inferring causal molecular networks: empirical assessment through a community-based effort

Inferring molecular networks is a central challenge in computational biology. However, it has remained unclear whether causal, rather than merely correlational, relationships can be effectively inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge that focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results constitute the most comprehensive assessment of causal network inference in a mammalian setting carried out to date and suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess the causal validity of inferred molecular networks

Inferring causal molecular networks: empirical assessment through a community-based effort

It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense

Selective lateral compartment neck dissection for thyroid cancer.

BACKGROUND: Compartment-oriented lymph node dissection in patients with thyroid cancer and macroscopic lymph node metastases reduces recurrence and improves survival. However, the extent of lymph node dissection remains controversial. The purpose of this study was to examine the results of selective lateral compartment neck dissection (LCND) for thyroid cancer. METHODS: We completed a retrospective review of patients with thyroid cancer who underwent selective LCND from 1992-2012 to determine the extent of lymph node resection, morbidity, recurrence, subsequent operations, mortality, and duration of follow-up. RESULTS: A total of 45 LCNDs (five bilateral) were performed in 40 patients, 35 with differentiated thyroid cancer (DTC) and five with medullary carcinoma. Nineteen LCNDs (42%) were completed at the time of thyroidectomy. Levels IIA, III, IV, and VB were included in 43 LCNDs (96%) and levels IIA, III, and IV in two LCNDs (4%). Morbidity included neck or ear numbness in 19 patients (48%), neuropathic symptoms in 14 (35%), Horner syndrome in two (5%), marginal mandibular nerve paresis in two (5%), and wound infection in one (3%). Recurrence rate was 25% (10 patients) and one or more reoperations were performed in seven patients (18%) with a mean follow-up of 58 ± 60 mo (range, 1-244 mo). There were 3 ipsilateral recurrences (8%) after 40 LCNDs for DTC. Four patients died from systemic disease: three with medullary carcinoma and one with PTC. CONCLUSIONS: Selective LCND is an effective therapeutic strategy for macroscopic lymph node metastases, with an 8% recurrence rate in the ipsilateral neck in patients with DTC. Neuropathic symptoms, however, remain an important source of morbidity

The role of transcervical thymectomy in patients with hyperparathyroidism.

BACKGROUND: The most common location for supernumerary or ectopic parathyroid glands is the thymus. METHODS: A review of patients who underwent parathyroidectomy for hyperparathyroidism from 1990 to 2010 was completed to determine indications for thymectomy, the yield of parathyroid tissue, and outcome of therapy. RESULTS: Seventy of 379 patients with hyperparathyroidism underwent parathyroidectomy and transcervical thymectomy. Intrathymic parathyroid tissue was present in 23 (33%) patients, including supernumerary glands in 8 patients (11%). Indications for thymectomy were renal hyperparathyroidism in 35 patients (50%) and primary hyperparathyroidism with a missing inferior gland in 20 patients (29%), an ectopic adenoma in 9 patients (13%), hyperplasia in 5 patients (7%), and carcinoma in 1 patient (1%). Cure rates were similar (96% and 98%; P = not significant) and only transient hypocalcemia was higher (51% vs 24%, P \u3c .05) after parathyroidectomy with thymectomy versus parathyroidectomy alone. CONCLUSIONS: Transcervical thymectomy results in a high yield of parathyroid tissue and is essential for cure of selected patients with hyperparathyroidism

Total thyroidectomy: is morbidity higher for Graves\u27 disease than nontoxic goiter?

BACKGROUND: Total thyroidectomy for treatment of Graves\u27 disease is controversial and much of the debate centers on the concern for complications. The purpose of this study was to evaluate the morbidity of total thyroidectomy for Graves\u27 disease and determine if it is different than for patients with nontoxic nodular goiter. METHODS: The rates of life threatening neck hematoma, recurrent laryngeal nerve (RLN) injury, transient hypocalcemia, and hypoparathyroidism were determined for consecutive patients with Graves\u27 disease treated with total thyroidectomy from 1996 to 2010. Results were compared with patients who underwent total thyroidectomy for nontoxic nodular goiter during the same period, matched for the weight of the excised thyroid gland. RESULTS: Total thyroidectomy was performed in 111 patients with Graves\u27 disease (group I) and 283 patients with nontoxic nodular goiter (group II). Parathyroid autotransplantation was performed in 31(28%) patients in group I and 98 (35%) patients in group II (P = NS). Comparative analysis of morbidity revealed no significant difference in neck hematoma, 0(0%) (I) versus 3(1%) (II); permanent RLN injury, 0(0%) (I) versus 2(1%) (II); and permanent hypoparathyroidism in 1(1%) (I) versus 1 (0.4%) (II) (P = NS). Transient hypocalcemia was more common in patients with Graves\u27 disease, 80(72%) (I) versus 170 (60%) (II) (P \u3c 0.05), but not when matched for thyroid weight. CONCLUSIONS: Total thyroidectomy can be performed with low morbidity in patients with Graves\u27 disease; only transient hypocalcemia occurred more often than in patients with nodular goiter. Total thyroidectomy should be presented as a therapeutic option for all patients with Graves\u27 disease

Delayed intracranial hemorrhage in elderly anticoagulated patients sustaining a minor fall.

BACKGROUND: Falls are a common cause of hospitalization, morbidity, and mortality among the elderly in the United States. Evidence-based imaging recommendations for evaluation of delayed intracranial hemorrhage (DICH) are not generally agreed upon. The purpose of this project was to evaluate the incidence of DICH detected by head computer tomography (CT) among an elderly population on pre-injury anticoagulant or antiplatelet (ACAP) therapy. METHODS: Data from a Level 1 Trauma Center trauma registry was used to assess the incidence of DICH in an elderly population of patients (≥65 years) who sustained a minor fall while on pre-injury ACAP medications. Counts and percentages are reported. RESULTS: Data on 1076 elderly trauma patients were downloaded, of which 838 sustained a minor fall and 513 were found to be using a pre-injury ACAP medication. One patient (0.46%) with a DICH was identified out of 218 patients who received a routine repeat head CT. Aspirin and warfarin were the most common pre-injury ACAP medications and 19.27% (42/218) of patients were found to be using multiple ACAP medications. CONCLUSIONS: Universal screening protocols promote immediate-term patient safety, but do so at a great expense with respect to health expenditures and increased radiation exposure. This analysis highlights the need for an effective risk assessment tool for DICH that would reduce the burden of unnecessary screenings while still identifying life-threatening intracranial hemorrhages in affected patients