Analysis, biomedicine, collaboration, and determinism challenges and guidance: wish list for biopharmaceuticals on the interface of computing and statistics.

I have personally witnessed processing advance from desk calculators and mainframes, through timesharing and PCs, to supercomputers and cloud computing. I have also witnessed resources grow from too little data into almost too much data, and from theory dominating data into data beginning to dominate theory while needing new theory. Finally, I have witnessed problems advance from simple in a lone discipline into becoming almost too complex in multiple disciplines, as well as approaches evolve from analysis driving solutions into solutions by data mining beginning to drive the analysis itself. How we do all of this has transitioned from competition overcoming collaboration into collaboration starting to overcome competition, as well as what is done being more important than how it is done has transitioned into how it is done becoming as important as what is done. In addition, what or how we do it being more important than what or how we should actually do it has shifted into what or how we should do it becoming just as important as what or how we do it, if not more so. Although we have come a long way in both our methodology and technology, are they sufficient for our current or future complex and multidisciplinary problems with their massive databases? Since the apparent answer is not a resounding yes, we are presented with tremendous challenges and opportunities. This personal perspective adapts my background and experience to be appropriate for biopharmaceuticals. In these times of exploding change, informed perspectives on what challenges should be explored with accompanying guidance may be even more valuable than the far more typical literature reviews in conferences and journals of what has already been accomplished without challenges or guidance. Would we believe that an architect who designs a skyscraper determines the skyscraper's exact exterior, interior and furnishings or only general characteristics? Why not increase dependability of conclusions in genetics and translational medicine by enriching genetic determinism with uncertainty? Uncertainty is our friend if exploited or potential enemy if ignored. Genes design proteins, but they cannot operationally determine all protein characteristics: they begin a long chain of complex events occurring many times via intricate feedbacks plus interactions which are not all determined. Genes influence proteins and diseases by just determining their probability distributions, not by determining them. From any sample of diseased people, we may more successfully infer gene probability distributions than genes themselves, and it poses an issue to resolve. My position is supported by 2-3 articles a week in ScienceDaily, 2011.

Intrathyroid parathyroid adenoma: incidence and location--the case against thyroid lobectomy.

OBJECTIVE: It has been taught that a missing parathyroid adenoma can be within the thyroid. Therefore, thyroid lobectomy is appropriate when an adenoma cannot be found. Unfortunately, this technique is often futile. The purpose of this study is to examine the frequency of unsuccessful thyroid lobectomy in parathyroid surgery and to look at the true incidence and location of intrathyroid parathyroid adenomas (iT-PAs). STUDY DESIGN: A retrospective chart review of 11,163 patients undergoing parathyroid surgery identifying the location of more than 40,000 parathyroid glands. SETTING: A tertiary care center specializing in parathyroid surgery. SUBJECTS AND METHODS: A total of 1163 reoperations for persistent primary hyperparathyroidism (PHPT) were examined for the incidence and outcomes of thyroid lobectomy performed to find iT-PA. A second study examined 10,000 patients undergoing first-time parathyroidectomy to classify the location and incidence of iT-PA. RESULTS: Thyroid lobectomy had been previously unsuccessfully performed in 77% cases of PHPT undergoing reoperation. Two or fewer glands were found in 82% prior to lobectomy. The adenoma was subsequently found on the lobectomy side in 64% and on the opposite side in 36%. True iT-PA occurred in only 0.7% of 10,000 primary cases. Another 1.2% were closely adherent to or partially within the thyroid substance. The most common location was the lower lateral quadrant of the thyroid. CONCLUSION: The incidence of true iT-PA is less than 1%, occurring in predictable locations. Thyroid lobectomy for a missing parathyroid adenoma is typically unsuccessful and should only rarely, if ever, be performed.

Calcium, parathyroid hormone, and vitamin D in patients with primary hyperparathyroidism: normograms developed from 10,000 cases.

OBJECTIVE: To better define the typical and atypical biochemical profiles of patients with surgically proven primary hyperparathyroidism. METHODS: In this single-center, prospectively conducted study of consecutive patients with surgically proven primary hyperparathyroidism over a 7-year period, we analyzed serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations. RESULTS: A total of 10 000 patients were included, and more than 210 000 calcium, parathyroid hormone, and 25-hydroxyvitamin D values were evaluated. Both calcium and parathyroid hormone levels demonstrated a Gaussian distribution with the average calcium concentration being 10.9 ± 0.6 mg/dL and the average parathyroid hormone concentration being 105.8 ± 48 pg/mL. The average highest calcium and parathyroid hormone concentrations were 11.4 ± 0.7 mg/dL and 115.3 ± 50 pg/mL, respectively. At least 1 calcium value of 11.0 mg/dL was seen in 87% of patients, but only 21% had 1 or more calcium value above 11.5 mg/dL. Only 7% had a single serum calcium level reaching 12.0 mg/dL. Normocalcemic hyperparathyroidism was seen in just under 3% of patients who had identical findings at surgery. An average parathyroid hormone concentration less than 65 pg/mL was seen in 16%, with 10% of patients who had no high parathyroid hormone values. The average 25-hydroxyvitamin D concentration was 22.4 ± 9 ng/mL, with levels decreasing as calcium levels increased (P<.001); 36% had 25-hydroxyvitamin D levels below 20 ng/mL. CONCLUSIONS: Patients with PHPT present with a number of distinct biochemical profiles, but as a group, they present with a near-normal Gaussian distribution of both calcium and parathyroid hormone levels. Either serum calcium or parathyroid hormone remained normal in 13% of patients, yet the findings at surgery are similar to those of patients with elevated calcium or parathyroid hormone. Low 25-hydroxyvitamin D is an expected finding in patients with PHPT, decreasing as serum calcium levels increase.

Postoperative calcium requirements in 6,000 patients undergoing outpatient parathyroidectomy: easily avoiding symptomatic hypocalcemia.

BACKGROUND: To determine the amount and duration of supplemental oral calcium for patients with varying clinical presentations discharged immediately after surgery for primary hyperparathyroidism. STUDY DESIGN: A 4-year, prospective, single-institution study of 6,000 patients undergoing parathyroidectomy for primary hyperparathyroidism and discharged within 2.5 hours. Based on our previous studies, patients are started on a sliding scale of oral calcium determined by a number of preoperative measures (ie, serum calcium, body weight, osteoporosis) beginning 3 hours postoperation and decreasing to a maintenance dose by week 3. Patients reported all hypocalcemia symptoms daily for 2 weeks. RESULTS: Seven parameters were found to have a substantial impact on the amount of calcium required to prevent symptomatic hypocalcemia: preoperative serum calcium >12 mg/dL, >13 mg/dL, and >13.5 mg/dL, bone density T score less than -3, morbid obesity, removal of >1 parathyroid, and manipulation/biopsy of all remaining glands (all p < 0.05). Each independent variable increased the daily calcium required by 315 mg/day. Using our scaled protocol, <8% of patients showed symptoms of hypocalcemia, nearly all of whom were successfully self-treated with additional oral calcium. Only 6 patients (0.1%) required a visit to the emergency room for IV calcium, all occurring on postoperative day 3 or later. CONCLUSION: After outpatient parathyroidectomy, a specific calcium protocol has been verified that eliminates development of symptomatic hypocalcemia in >92% of patients, identifies patients at high risk for hypocalcemia, and allows self-medication with confidence in a predictable fashion for those patients in whom symptoms develop.

Content validity of manual spinal palpatory exams - A systematic review.

BACKGROUND: Many health care professionals use spinal palpatory exams as a primary and well-accepted part of the evaluation of spinal pathology. However, few studies have explored the validity of spinal palpatory exams. To evaluate the status of the current scientific evidence, we conducted a systematic review to assess the content validity of spinal palpatory tests used to identify spinal neuro-musculoskeletal dysfunction. METHODS: Review of eleven databases and a hand search of peer-reviewed literature, published between 1965-2002, was undertaken. Two blinded reviewers abstracted pertinent data from the retrieved papers, using a specially developed quality-scoring instrument. Five papers met the inclusion/exclusion criteria. RESULTS: Three of the five papers included in the review explored the content validity of motion tests. Two of these papers focused on identifying the level of fixation (decreased mobility) and one focused on range of motion. All three studies used a mechanical model as a reference standard. Two of the five papers included in the review explored the validity of pain assessment using the visual analogue scale or the subjects' own report as reference standards. Overall the sensitivity of studies looking at range of motion tests and pain varied greatly. Poor sensitivity was reported for range of motion studies regardless of the examiner's experience. A slightly better sensitivity (82%) was reported in one study that examined cervical pain. CONCLUSIONS: The lack of acceptable reference standards may have contributed to the weak sensitivity findings. Given the importance of spinal palpatory tests as part of the spinal evaluation and treatment plan, effort is required by all involved disciplines to create well-designed and implemented studies in this area.